Dopamine agonists

ABSTRACT

Novel compounds having the formula ##STR1## and the pharmaceutically acceptable salts, esters and amides thereof, wherein 
     A is --O--, --S-- or --CR 2  R 8  --; 
     R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are specifically defined; and 
     up to one combination of (a) R 2  and R 5 , (b) R 5  and R 6 , (c) R 5  and R 7 , (d) R 6  and R 7 , and (e) R 7  and Y, taken together with the atoms to which they are attached, may form a ring, the compounds being useful for treating dopamine-related neurological, psychological and cardiovascular disorders as well as in the treatment of cognitive impairment, attention deficit disorder, and substance abuse and other addictive behavior disorders. 
     Also disclosed are intermediates and processes useful in the preparation of the above compounds.

This application is a divisional of U.S. Ser. No. 08/442,236, filed May30, 1995, pending, which is a continuation-in-part of U.S. applicationSer. No. 07/998,161, filed on Dec. 29, 1992, now abandoned, which is acontinuation-in-part of International Application No. PCT/US90/02864,filed on May 22, 1990, now abandoned, which is a divisional of07/776,258 filed Nov. 27, 1991, now abandoned which is acontinuation-in-part of U.S. application Ser. No. 07/359,448, filed May31, 1989, and issued on Oct. 16, 1990 as U.S. Pat. No. 4,963,568.

TECHNICAL FIELD

This invention relates to novel compounds which are selective dopamineagonists useful for treating dopamine-related neurological,psychological, cardiovascular, cognitive and behavioral disorders.

BACKGROUND OF THE INVENTION

Dopamine is an important neurotransmitter in the central nervous system(CNS), and also has several important roles in the peripheral nervoussystem such as in the control of the supply of blood to the kidneys andin autonomic ganglion transmission.

It is now widely accepted that dopamine receptors in the CNS can bedivided into two general categories, designated D-1 and D-2 receptors.The division was originally based on biochemical and pharmacologicaldifferences between the two receptor types, but further evidencesupporting this division has recently come from study of the molecularbiology of dopamine receptors in the CNS. The dopamine D-1 receptor islinked to the enzyme adenylate cyclase through a stimulatory G protein,such that stimulation of this receptor by dopamine or a dopamine D-1receptor agonist causes an increase in the production of 3',5'-cyclicadenosine monophosphate (cAMP).

The D-2 receptor, on the other hand, also regulates important functionalactivity within the CNS, although the biochemical events which followstimulation of this receptor by dopamine or a D-2 receptor agonist arenot as well understood. Autoreceptors on dopaminergic neurons which havethe pharmacological properties of D-2 receptors are thought to controlboth the firing rate of these cells as well as the release of dopaminefrom the nerve terminals. It is also known that stimulation of the D-2receptors in the intermediate lobe of the pituitary gland causes adecrease in cAMP production and that stimulation of the D-2 receptors onthe mammotrophs of the anterior pituitary gland suppresses prolactinsecretion. Dopaminergic neurons are also affected by and interact withother neurotransmitter systems in the CNS, as for example D-2 receptorson the cholinergic interneurons in the striatum (one of the componentsof the basal ganglia) regulating the release of acetylcholine from thesecells.

Dopamine involvement has been proposed for several diverse neurologicaland psychological disorders. One disorder involving dopamine isParkinson's Disease. Dopamine occurs at high concentration within thenerve terminals in the basal ganglia of the mammalian brain. In theearly 1960's, the loss of striatal dopamine was established as achemical marker of Parkinson's Disease. This deficiency is still thoughtto be primary to the etiology of the disease state.

L-DOPA (3,4-dihydroxyphenylalanine), which is used in conjunction with aperipheral aromatic amino acid decarboxylase inhibitor and oftensupplemented with anticholinergic agents, has been shown to be useful inthe treatment of Parkinson's Disease. The response to L-DOPA is thoughtto be a result of the conversion of L-DOPA to dopamine within thestriatum, and is linked to stimulation of both the D-1 and D-2receptors.

The success of L-DOPA therapy has led to the testing of other compoundscapable of mimicking the post-synaptic receptor actions of dopamine.Such direct-acting agents might offer the therapeutic advantages ofgreater potency, increased duration of action, or fewer side effectsover L-DOPA. For example, bromocryptine, the direct-acting dopamineagonist most widely used in the treatment of Parkinson's Disease, lowersthe amount of L-DOPA required to achieve the maximal therapeuticresponse and allows for a delay in the onset of L-DOPA therapy. However,the response to bromocryptine alone is not as great as that observedwith L-DOPA.

Another disorder in which dopamine has been implicated is schizophrenia.Psychoses are serious psychiatric illnesses characterized by abnormalbehavior which may include delusions, hallucinations, violence, maniaand serious long-lasting depression. Of these, schizophrenia is the mostcommon, involving disturbance of thought processes, hallucinations andloss of touch with reality. The theory of schizophrenia as a disease ofthe CNS was first formalized by Kraepelin and Bleuler in the early1900's. It was not until chlorpromazine was discovered by Delay andDaniker in the early 1950's, however, that drug management of thisdisease was possible.

The pioneering work of Carlsson and others led to the now widely-helddopamine theory of schizophrenia. According to this theory,schizophrenia is caused by an excess of dopamine in the brain. Severallines of evidence support this hypothesis. For example, chronic abuse ofstimulants such as amphetamines, known to enhance dopaminergic activityin the brain, can lead to a paranoid psychosis that is almostindistinguishable from classic paranoid schizophrenia. The mechanism ofaction proposed for drugs with anti-schizophrenic activity is theblockade by these compounds of the dopamine receptors and, consequently,the prevention of excess receptor stimulation. In the mid 1970's, it wasobserved that virtually all of the currently used antipsychotic agentscould displace radiolabeled haloperidol (a dopamine antagonist) fromstriatal dopamine receptors with a good correlation between averageeffective clinical dose and drug binding affinity.

Unfortunately, the currently-available antipsychotic agents frequentlyproduce undesirable side-effects, the most common of which are theso-called extrapyramidal effects that include bizarre involuntarymovements and Parkinson-like effects. Sedation and hypotension are alsocommon side-effects. Because of these often severe side-effects and thehigh incidence of patients unresponsive to currently-available drugs,more potent and more selective agents are needed.

It is also recognized that depressive conditions and related affectivedisorders result from a reduction in the central nervous system ofcertain biogenic amine neurotransmitters such as dopamine (D),noradrenaline (NA) and serotonin (5-HT). Affective disorders arecharacterized by changes in mood as the primary clinical manifestation.Disturbances of mood are the most common psychiatric disorders inadults, with 18-23% of women and 8-11% of men experiencing at least onemajor depressive episode. Currently-available antidepressant drugs workprimarily by raising the levels of the biogenic amine neurotransmitterseither by inhibition of the neuronal uptake of the neurotransmitters orby inhibition of the metabolic enzymes responsible for converting thebiogenic amines to inactive metabolites. Unfortunately, there are majordrawbacks to the use of currently-available agents for treatingaffective disorders. For example, no antidepressant drug to date hasproven to be superior to electroconvulsive shock therapy in thetreatment of severe, suicidal depression. Other problems with the use ofavailable drugs are delayed onset of activity, poor efficacy,anticholinergic effects at therapeutic doses, cardiotoxicity,convulsions and the danger of taking a fatal overdose. There also existsa large number of untreated individuals and treatment-resistant patientsin need of effective therapy. A role for direct-acting dopamine agonistsin antidepressant therapy has been suggested based on the effectsobserved for several dopamine agonists in various animal models used forpredicting antidepressant activity such as the "mouse behavioral despairtest".

A role for dopamine has been established in several other neurologicalfunctions, such as cognitive function and attention mechanisms. Animalstudies implicate dopamine in attention-related behaviors involvingsearch and exploratory activity, distractibility, response rate,discriminability and the switching of attention. A therapeutic role inthe treatment of cognitive impairment and attention deficit disordershas therefore been proposed and is under active investigation forcompounds which mimic the receptor activity of dopamine.

Dopamine has been also used in the treatment of shock, congestive heartfailure and renal failure. Stimulation of the peripheral D-1 receptorscauses vasodilation, particularly in the renal and mesenteric vascularbeds where large numbers of these receptors are found. The utility ofdopamine has been limited, however, by its ability to causevasoconstriction at higher concentrations, presumably due to itssecondary effects on adrenergic receptors and by its emetic effects dueto peripheral D-2 stimulation. Agents selective for the peripheral D-1receptors may offer significant advantages over currently usedtreatments for these and other related disorders.

Published evidence suggests that dopamine also has a central role in thebrain's reward system. For example, it has been reported that animalstrained to self-administer cocaine will increase their consumption ofthis drug after treatment with either a D-1 or a D-2 receptorantagonist. It was proposed that the animals would increase the amountof cocaine administered in order to maintain the elevated dopaminelevels responsible for the drugs euphorigenic and reinforcingproperties. The dopamine D-1 agonist, SKF 38393, has been reported todecrease food intake by rats presumably by direct action of the drug onneural feeding mechanisms. Because of this interrelationship betweendopamine and reward, dopaminergic agents could be useful for thetreatment of substance abuse and other addictive behavior disordersincluding cocaine addiction, nicotine addiction and eating disorders.

Dopaminergic agents such as the compounds of the present invention thatmimic the actions of dopamine and show selectivity for the differentdopamine receptor subtypes are needed in order to obtain the anticipatedphysiological responses discussed above, separate from other possiblyless desirable effects.

Related 5-hydroxy dopaminergic compounds were reported in U.S. Pat. No.4,994,486, which is also a continuation-in-part of U.S. application Ser.No. 359,448, and compounds having somewhat related structures to thenovel compounds of the instant invention have been disclosed inpublished European Patent Applications Nos. 321968 and 325963 and inFrench Patent No. 2,407,212. However, the 1-aminomethyltetrahydronaphthalene derivatives of EP 0321968 are unsubstituted at the3-position and are substituted on the amino group with an n-propyl groupor an n-propyl and an additional phenoxyethyl group; the 1-aminomethyltetrahydronaphthalene derivatives of EP 0325963 are substituted on theamino group with an aryl-substituted or heterocycle-substituted alkylgroup; and in the 1-aminoalkyl-substituted isochroman and thioisochromancompounds of the French Patent, the amino group of the 1-amino alkylgroup must be in a 6-membered ring containing one or two nitrogen atomsand is further substituted with a nitrogen substituent, an aryl group ora benzimidazole group.

SUMMARY OF THE INVENTION

In on aspect of the present invention are disclosed dopaminergiccompounds of the formula I: ##STR2## as well as pharmaceuticallyacceptable salts, esters and amides thereof, wherein:

A is --O--, --S--, or --CR² R⁸ --, where R² and R⁸ are as defined below;

R¹ is selected from hydrogen and a readily-cleavable group, as definedbelow; or is a catechol-protecting group, as defined below;

R² is selected from hydrogen, methyl, ethyl, hydroxymethyl,hydroxyethyl, halomethyl, haloethyl, aminomethyl and aminoethyl, or,taken together with R⁵ and the atoms to which each is attached (as wellas any intervening atoms) forms a 5- or 6-membered ring containing onlyone heteroatom, the nitrogen shown above in formula I;

R³ is selected from:

C₄ -C₁₀ -alkyl, as defined below,

substituted C₁ -C₅ -alkyl, as defined below,

C₂ -C₁₂ -alkenyl, as defined below,

substituted C₂ -C₅ -alkenyl, as defined below,

C₂ -C₁₂ -alkynyl, as defined below,

substituted C₂ -C₅ -alkynyl, as defined below,

cyclo-C₃ -C₁₀ -alkyl, as defined below,

substituted cyclo-C₃ -C₁₀ -alkyl, as defined below,

carbocyclic-C₆ -C₁₀ -aryl, as defined below,

substituted carbocyclic-C₆ -C₁₀ -aryl, as defined below,

carbocyclic-C₆ -C₁₀ -aryloxy-C₁ -C₅ -alkyl, as defined below,

substituted carbocyclic-C₆ -C₁₀ -aryloxy-C₁ -C₅ -alkyl, as definedbelow,

carbocyclic-C₆ -C₁₀ -aryl-C₁ -C₅ -alkyl, as defined below,

substituted carbocyclic-C₆ -C₁₀ -aryl-C₁ -C₅ -alkyl, as defined below,

Het, as defined below,

substituted Het, as defined below,

Het-C₁ -C₅ -alkyl, as defined below, and

substituted Het-C₁ -C₅ -alkyl, as defined below,

or, taken together with R⁴ and the atom to which both are attached,forms a spirocyclo-C₃ -C₁₀ -alkyl ring, as defined below;

R⁴ is selected from hydrogen and C₁ -C₁₀ -alkyl, or, taken together withR³ and the atom to which both are attached, forms a spirocyclo-C₃ -C₁₀-alkyl ring, or, taken together with R⁹, forms a bond;

R⁵ is selected from:

hydrogen,

C₁ -C₃ -alkyl,

hydroxy-C₂ -C₃ -alkyl,

amino-C₂ -C₃ -alkyl,

C₁ -C₃ -alkoxy-C₂ -C₃ -alkyl, as defined below,

C₂ -C₃ -alkenyl,

C₂ -C₃ -alkynyl,

cyclo-C₃ -C₅ -alkyl,

C₁ -C₈ -alkanoyl, as defined below,

a readily-cleavable group,

an amino acid, as defined below, and

a dipeptide, as defined below;

or, taken together with one of R⁶ and R⁷ and the atoms to which each isattached (as well as any intervening atoms), forms a pyrrolidine ring;or, when A is --CR² R⁸ -- and R⁸ is hydrogen, is taken together with R²and the atoms to which each is attached (as well as any interveningatoms) to form a 5- or 6-membered ring containing only one heteroatom,namely, the nitrogen shown in formula I;

R⁶ is selected from hydrogen and C₁ -C₃ -alkyl; or, taken together withR⁵ and the atom to each is attached, forms a pyrrolidine ring;

R⁷ is hydrogen or C₁ -C₅ -alkyl; or, taken together with R⁵ and theatoms to which each is attached (as well as any intervening atoms),forms a pyrrolidine ring; or, taken together with Y and the atoms towhich each is attached (as well as any intervening atoms), forms a 5-,6- or 7-membered carbocyclic ring;

R⁸ is hydrogen or, taken together with R¹⁰, forms a bond;

R⁹ is hydrogen or, taken together with R⁴, forms a bond;

R¹⁰ is hydrogen or, taken together with R⁸, forms a bond;

X is selected from hydrogen, halogen, methyl and ethyl;

Y is selected from hydrogen, halogen, methyl and ethyl; or, takentogether with R⁷ and the atoms to which each is attached (as well as anyintervening atoms), forms a 5-, 6- or 7-membered carbocyclic ring.

The compounds of the present invention are limited, however, in that (i)at least one of X and Y must be hydrogen when Y is not combined in aring; and (ii) only one of the following combinations of groups and theatoms to which they are attached may be taken together to form a ring asdescribed above: (a) R² and R⁵, (b) R⁵ and R⁶, (c) R⁵ and R⁷, (d) R⁶ andR⁷, and (e) R⁷ and Y.

The compounds of formula I have the ability to bind and activatedopamine receptors in the central and peripheral nervous systems, thusmimicing the activity of dopamine, and are therefore expected to beuseful in the treatment of dopamine-related neurological, psychologicaland cardiovascular disorders, as well as in the treatment of substanceabuse and other addictive behavior disorders, cognitive impairment andattention deficit disorder.

In a second aspect of the present invention, pharmaceutical compositionsare disclosed which comprise a therapeutically-effective amount of thecompound of formula I and a pharmaceutically-acceptable carrier ordiluent.

DETAILED DESCRIPTION OF THE INVENTION

Representative of the compounds of the invention are those compounds offormula I in which A is --O--; R⁹ is hydrogen; and R¹, R³, R⁴, R⁵, R⁶,R⁷, R¹⁰, X and Y are as defined above.

In another particular embodiment of the invention are compounds offormula I in which A is --S--; R⁵ is hydrogen, C₁ -C₃ -alkyl or C₁ -C₈-alkanoyl; R⁶, R⁷, and R⁹ are hydrogen; and R¹, R³, R⁴, R¹⁰, X and Y areas described above.

In a further particular embodiment of the invention are compounds offormula I in which A is --CR² R⁸ --; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, X and Y are as defined above.

In a preferred embodiment of the invention are compounds of formula I inwhich (a) A is --CR² R⁸ --; (b) R² and R⁵, taken together with the atomsto which each is attached, form a 5- or 6-membered ring; (c) R⁷ and R⁹are each hydrogen; and (d) R¹, R³, R⁴, R⁶, R⁸, R¹⁰, X and Y are asdefined above. Such compounds have the formula: ##STR3## where w is 1 or2.

In another preferred embodiment of the invention are compounds offormula I in which (a) R⁷ and Y, taken together with the atoms to whicheach is attached, form a 5-, 6- or 7-membered ring; and (b) R¹, R², R³,R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰ and X are as defined above. Such compounds havethe formula: ##STR4## where z is 1, 2 or 3.

As to each of the above embodiments, preferred compounds include (i)those in which R³ is selected from C₄ -C₁₀ -alkyl, substituted C₁ -C₅-alkyl, cyclo-C₃ -C₁₀ -alkyl, substituted cyclo-C₃ -C₁₀ -alkyl,carbocyclic-C₆ -C₁₀ -aryl, substituted carbocyclic-C₆ -C₁₀ -aryl,carbocyclic-C₆ -C₁₀ -aryl-C₁ -C₅ -alkyl, substituted carbocyclic-C₆ -C₁₀-aryl-C₁ -C₅ -alkyl, Het, substituted Het, Het-C₁ -C₅ -alkyl, andsubstituted Het-C₁ -C₅ -alkyl, or, taken together with R⁴ and the atomto which R³ and R⁴ are both attached, forms a spirocyclo-C₃ -C₁₀ -alkylring, and/or (ii) those in which R⁵ and R⁶ are hydrogen, or where one ofR⁵ and R⁶ is methyl and the other is hydrogen.

The following compounds are representative of the compounds of theinvention:

1-Aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene;

[1,3-cis]1-Aminomethyl-3-n-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclopentylmethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclooctyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-n-Butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

5,6-Bis(acetoxy)-1-(alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene;

5,6-Bis(acetoxy)-1-(g-glutamyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene;

5,6-Bis(acetoxy)-1-(alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene;

5,6-Bis(acetoxy)-1-(methionyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene;

1-(Alanyl-alanyl)aminomethyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphthalene;

[1R*,2S*,3S*]1-Aminomethyl-5,6-dihydroxy-2-(2-hydroxy-1-ethyl)-3-phenyl-1,2,3,4-tetrahydronaphthalene;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-hydroxyphenyl)-1,2,3,4-tetrahydronaphthalene;

1-Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene;

[1,3-cis]1-Aminomethyl-3-benzyloxymethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(diphenyl)methyl-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(3'-methyl-2'-n-pentyl)-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(1'-but-3'-ene)-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-(6'-methyl-2'-hept-5'-ene)-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclooctyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R*,8S*,9aR*]1-Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene;

[1S*,8S*,9aR*]1-Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene;

6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e]isoindole;

[1R,3S]3-(1-Adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1-Aminomethyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphthalene;

5-Aminomethyl-7-(2-naphthyl)-7,8-dihydronaphthalene-1,2-diol;

5-Aminomethyl-7-(1-naphthyl)-7,8-dihydronaphthalene-1,2-diol;

1-Aminomethyl-5,6-bis(butoxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(isobutoxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(methylsuccinyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Acetylaminomethyl-5,6-bis(acetyloxy)-3-phenyl-3,4-dihydronaphthalene;

5-N-Acetylmethylaminomethyl-3-phenyl-7,8-dihydronaphthalene-1,2-diol;

1-Aminomethyl-5,6-bis(propionyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(phenylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(methoxycarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(isopropylsuccinyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(dimethylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(beta-alanoyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(ethoxycarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(benzylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(methylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

5,6-Bis(acetyloxy)-1-t-butyloxycarbonylaminomethyl-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(p-methoxybenzoyloxy)-3-phenyl-3,4-dihydronaphthalene;

1-Aminomethyl-5,6-bis(methylaminocarbonyloxy)-3-phenyl-3,4-dihydronaphthalene;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzothiopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-methoxyphenyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-1-methylaminomethyl-3-phenyl-3,4-dihydro-1H-2-benzothiopyran;

[1,3-cis]3-(1-Adamantyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-trans]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-trans]1-Aminomethyl-5,6-dihydroxy-3-(4-methoxybenzyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-3-(4-methoxybenzyl)-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1S,3S]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R,3R]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R,2'R,3S]5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(2-(1-oxoisoindole)methyl)-3,4-dihydro-1H-2-benzopyran;

[1R,2'S,3S]5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-1-methylaminomethyl-3-phenyl-3,4-dihydro-1H-2-benzopyran;

5-Phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

2-Methyl-5-phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

[1'S,1R,3S]3,4-Dihydro-5,6-dihydroxy-1-methylaminomethyl-3-phenyl-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclohexylmethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-isobutyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantylmethyl)-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantylmethyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-Cyclohexylmethyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Allylaminomethyl-3-n-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-(2-cyclohexylethyl)-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(ethylmalonamidomethyl)-3,4-dihydro-1H-2benzopyran;

1'-Aminomethyl-5',6'-dihydroxyspiro[cycloheptane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

1'-Aminomethyl-5',6'-dihydroxyspiro[cyclooctane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

5',6'-Dihydroxy-1'-methylaminomethylspiro[cycloheptane-1,3'-(3',4'-dihydro-1'H-2'benzopyran)];

[1,3-cis]3-(1-Adamantyl)-1-aminomethyl-8-bromo-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

5'6'-Dihydroxy-1'-methylaminomethylspiro[cyclooctane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

[1,3-cis]1-Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

1'-Aminomethyl-5',6'-dihydroxyspiro[tetrahydropyran-4,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

5',6'-Dihydroxy-1'-methylaminomethylspiro[tetrahydropyran-4,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-trans]1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1S,3R]5,6-dihydroxy-3-phenyl-1-(2(R)-pyrrolidinyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(4-ethoxy-2,3,5,6-tetrafluorophenylmethyl)-3,4-dihydro-1H-2-benzopyran;

5'-Aminomethylspiro[cyclohexane-1,7'-(7',8'-dihydronaphthalene)]-1',2'-diol;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-trifluoromethylphenyl)-3,4-dihydro-1H-2-benzopyran;

5'-Aminomethylspiro[cyclohexane-1,7'-(5',6',7',8'-tetrahydronaphthalene)]-1',2'-diol;

[1R,3S]1-Aminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-Allyl-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

2'-Methylspiro[cyclohexane-1,5'-(1',2',3',4',5',6'-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

Spiro[cyclohexane-1,5'-(1',2',3',4',5',6'-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-dimethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-1-methylaminomethyl-3-n-pentyl-3,4-dihydro-1H-2-benzopyran;

(5R)-5-Phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

Spiro[cyclopentane-1,5'-(1',2',3',4',5',6'-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

2'-Methylspiro[cyclopentane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]-7',8'-diol;

5'-Aminomethylspiro[cyclopentane-1,7'-(5,6,7',8'-tetrahydro-naphthalene)]-1',2'-diol;

[1R,3S]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-(1-Adamantyl)-5,6-dihydroxy-7-fluoro-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-ethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1R,3S]1-Allylaminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-t-Butylmethyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

5'-Aminomethylspiro[cycloheptane-1,7'-(5',6',7',8'-tetrahydronaphthalene)]-1',2'-diol;

5'-Aminomethylspiro[cycloheptane-1,7'-(7',8'-dihydronaphthalene)]-1',2'-diol;

Spiro[cycloheptane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]-7',8'-diol;

[1R,3S]1-Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-t-butylmethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3R-but-1-enyl))-3,4-dihydro-1H-2-benzopyran;

5-Aminomethyl-7-t-butyl-7,8-dihydronaphthalene-1,2-diol;

[5,7-cis]-5-Aminomethyl-7-t-butyl-5,6,7,8-tetrahydronaphthalene-1,2-diol;

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-n-propylaminomethyl-3,4-dihydro-1H-2-benzopyran;

5-t-Butyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

5-Cyclohexyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

5-Cyclopentylmethyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

[1R,3S]3-(1-Adamantyl)-5,6-dihydroxy-1-dimethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

Spiro[cyclooctane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]-7',8-diol;

[1R,3R]1-Aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Aminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Methylaminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1'-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclononane-1,3'-(1'H-2'-benzopyran)];

[1,3-cis]1-Aminomethyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-(1-phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

3',4'-Dihydro-5',6'-dihydroxy-1'-methylaminomethylspiro[cyclononane-1,3'-(1'H-2'-benzopyran)];

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1R,2S-1-(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1-Aminomethyl-3-adamantyl-5,6-dihydroxy-3,4-dihydronaphthalene;

1'-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclononane-1,3'-naphthalene];

1-Aminomethyl-3-(2,2-dimethylpropyl)-5,6-dihydroxy-3,4-dihydronaphthalene;

1'-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclodecane-1,3'-naphthalene];

1-Aminomethyl-3-adamantyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene;

1'-Aminomethyl-1',2',3',4'-tetrahydro-5',6'-dihydroxyspiro[cyclononane-1,3'-naphthalene];

1'-Aminomethyl-1',2',3',4'-tetrahydro-5',6'-dihydroxyspiro[cyclodecane-1,3'-naphthalene];

5-Adamantyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol;

(5R)-1,2,3,4,5,6-Hexahydro-5-phenylbenzo[h]isoquinoline-7,8-diol;

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxyspiro[cyclodecane-1,5'-benzo[h]-isoquinoline];

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxyspiro[cyclononane-1,5'-benzo[h]-isoquinoline];

5-(2,2-Dimethylpropyl)-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol;

5-Butyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol;

5-(2,2-Dimethylpropyl)-1,2,3,4,5,6-hexahydro-2-methylbenzo[h]isoquinoline-7,8-diol;

5-(Cyclopentylmethyl)-1,2,3,4,5,6-hexahydro-2-methylbenzo[h]isoquinoline-7,8-diol;

(5R)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

(5S)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cyclononane-1,5'-benzo[h]isoquinoline];

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1,5'-benzo[h]isoquinoline];

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cyclooctane-1,5'-benzo[h]isoquinoline];

2-Ethyl-1',2',3',4',5',6'-hexahydro-7',8'-dihydroxy-spiro[cycloheptane-1,5'-benzo[h]isoquinoline];and

1',2',3',4',5',5a',6',8a'-Octahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1,5'-benzo[h]isoquinoline];

and pharmaceutically acceptable salts thereof.

The following compounds are representative of the preferred compounds ofthe invention:

[1,3-cis]1-Aminomethyl-3-n-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclopentylmethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclooctyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-n-Butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-3-phenyl-1-(2'R*-pyrrolidinyl)-1,2,3,4-tetrahydro-naphthalene;

[1,3-trans]5,6-Dihydroxy-3-phenyl-1-(2'R*-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalene;

[1,3-cis]5,6-Dihydroxy-1-methylaminomethyl-3-phenyl-1,2,3,4-tetrahydronaphthalene;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-naphthalene;

1-Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene;

[1,3-cis]1-Aminomethyl-3-benzyloxymethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R*,8S*,9aR*]1-Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene;

[1S*,8S*,9aR*]1-Amino-5,6-dihydroxy-2,3,7,8,9,9a-hexahydro-8-phenylphenalene;

6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e]isoindole;

[1R,3S]3-(1-Adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1-Aminomethyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphthalene;

Spiro[cyclopentane-1,5'-(1',2',3',4',5',6',-hexahydrobenzo[h]isoquinoline)]-7',8'-diol;

Spiro[cyclohexane-1,5'-(1',2',3',4',5',6',-hexahydrobenzo[h]isoquinoline)]-7',8'-diol;

Spiro[cycloheptane-1,5'-(1',2',3',4',5',6',-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

Spiro[cyclooctane-1,5'-(1',2',3',4',5',6',-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

5-Phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

2-Methyl-5-phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

Spiro[cyclooctane-1,5'-(1',2',3',4',5',6',-hexahydro-benzo[h]isoquinoline)]-7',8'-diol;

5-Cyclohexyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

5-Cyclopentylmethyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-methoxyphenyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1R,3S]5,6-Dihydroxy-1-methylaminomethyl-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclohexylmethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-isobutyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantylmethyl)-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-(1-Adamantylmethyl)-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-Cyclohexylmethyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

1'-Aminomethyl-5',6'-dihydroxyspiro[cycloheptane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

1'-Aminomethyl-5',6'-dihydroxyspiro[cyclooctane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

5',6'-Dihydroxy-1'-methylaminomethylspiro[cycloheptane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

5',6'-Dihydroxy-1'-methylaminomethylspiro[cyclooctane-1,3'-(3',4'-dihydro-1'H-2'-benzopyran)];

[1,3-cis]1-Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-trans]1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(4-ethoxy-2,3,5,6-tetrafluorophenylmethyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3-trifluoromethylphenyl)-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-Allyl-1-aminomethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-t-Butyl-5,6-dihydroxy-1-dimethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]5,6-Dihydroxy-1-methylaminomethyl-3-n-pentyl-3,4-dihydro-1H-2-benzopyran;

[1R,3S]1-Aminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-(1-Adamantyl)-5,6-dihydroxy-7-fluoro-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-t-Butyl-5,6-dihydroxy-1-ethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]3-t-Butylmethyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Allylaminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-t-butylmethyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran;

[1,3-cis]1-aminomethyl-5,6-dihydroxy-3-(3R-but-1-enyl))-3,4-dihydro-1H-2-benzopyran;

[1R,3S]3-(1-Adamantyl)-5,6-dihydroxy-1-dimethylaminomethyl-3,4-dihydro-1H-2-benzopyran;

[1R,3R]1-Aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Aminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Methylaminomethyl-3-cyclopentylmethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-dimethylamino)methyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1'-Aminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclononane-1,3'-(1'H-2'-benzopyran)];

[1,3-cis]1-Aminomethyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-Aminomethyl-3-(1-phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1'-Methylaminomethyl-3',4'-dihydro-5',6'-dihydroxyspiro[cyclononane-1,3'-(1'H-2'-benzopyran)];

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-phenylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1R,2S-1-(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

(5R)-1,2,3,4,5,6-hexahydro-5-phenylbenzo[h]isoquinoline-7,8-diol;

5-Butyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diol;

(5R)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

(5S)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1,5'-benzo[h]isoquinoline];and

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cyclooctane-1,5'-benzo[h]isoquinoline];

and pharmaceutically acceptable salts thereof.

The following compounds are representative of the more preferredcompounds of the invention:

[1R,3S]3-(1-Adamantyl)-1-aminomethyl-5,6-dihydroxy-7-fluoro-3,4-dihydro-1H-2-benzopyran;

2-Methyl-5-phenyl-1,2,3,4,5,6,-hexahydrobenzo[h]isoquinoline-7,8-diol;

(5R)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

(5S)-1,2,3,4,5,6-hexahydro-2-methyl-5-phenylbenzo[h]isoquinoline-7,8-diol;

1',2',3',4',5',6'-Hexahydro-7',8'-dihydroxy-2'-methylspiro[cycloheptane-1,5'-benzo[h]isoquinoline];

[1R,3R]1-Aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Aminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1R,3R]1-Methylaminomethyl-3-(2-methylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-(1-methylcyclohexyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

1R,3S-1-(N,N-Dimethylamino)methyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;and

[1,3-cis]1-(N,N-Dimethylamino)methyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran;

and pharmaceutically acceptable salts thereof.

In another aspect of the present invention are disclosed syntheticintermediates which are useful in the preparation of the compounds offormula I. Such intermediate compounds have the formula Ia: ##STR5##where A is --O-- or --S--;

R¹ is a catechol-protecting group;

R³ is selected from C₄ -C₁₀ -alkyl, substituted C₁ -C₅ -alkyl, C₂ -C₁₂-alkenyl,C₂ -C₁₂ -alkynyl, cyclo-C₃ -C₁₀ -alkyl, carbocyclic-C₆ -C₁₀-aryl, carbocyclicC₆ -C₁₀ -aryl-C₁ -C₅ -alkyl, and Het; and

R⁴ is selected from hydrogen and C₁ -C₁₀ -alkyl;

or, taken together, R³ and R⁴ and the carbon atom to which both areattached form a spiro-C₃ -C₁₀ -cycloalkyl ring.

In a further aspect of the present invention is disclosed a novelprocess for preparing the compounds of formula Ia, comprising reactingan intermediate having the formula: ##STR6## where A, R¹, R³, and R⁴ areas described above in connection with formula Ia, withN-formylaminoacetaldehyde dimethyl acetal in the presence of an acidcatalyst selected from boron trifluoride etherate, zinc triflate,trimethylsilyl triflate and methanesulfonic acid.

In yet another aspect of the present invention are disclosed chiralintermediate compounds useful in the preparation of the compounds offormula I. Such chiral compounds have the formula Ib: ##STR7## where R¹is a catechol-protecting group and R¹⁸ is substituted C₃ -C₉ -alkyl.

In still another aspect of the present invention is disclosed a novelprocess for preparing the chiral compounds of formula Ib, comprising thesteps of (a) reacting an intermediate having the formula: ##STR8## whereR¹ is a catechol-protecting group, with a strong base to form a chiralepoxide of the formula: ##STR9## and (b) reacting the epoxide with anorganometallic substituted C₃ -C₉ -alkyl compound in a non-polar organicsolvent to give a compound of formula 1b.

Certain compounds of this invention may possess one or more asymmetriccenters and may exist in optically active forms. Additional asymmetriccenters may be present in a substituent group, such as an alkyl group.Pure d-isomers and pure l-isomers, racemic mixtures of the isomers, andmixtures thereof are intended to be within the scope of this invention.In particular, the stereochemistry at the 1- and 3-positions, as shownin formula I, may independently be either [R] or [S] unless specificallynoted otherwise. Chiral forms of certain compounds of this invention arecontemplated and are specifically included within the scope of thisinvention.

The term "alkanoyl", as used herein, means a carbonyl group linked to analkyl group, as defined below, of the size indicated.

The term "alkanoylamino" means an alkanoyl group, as defined above, ofthe size indicated, connected to an amino group.

The term "alkenyl" means straight or branched carbon chain radicals ofthe size indicated containing at least one carbon-to-carbon double bond.Representative of such radicals are ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, 2-ethylhexenyl, n-octenyl, 2,4-dimethylpentenyl,and the like.

The term "alkoxy" means an oxygen atom linked by an ether bond to analkyl group, as defined below, of the size indicated. Examples of alkoxygroups are methoxy, ethoxy, t-butoxy, and the like.

The term "alkyl" means a straight- or branched-chain carbon radical ofthe size indicated. Representative of alkyl radicals are methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,2-ethylhexyl, n-octyl, 2,4-dimethylpentyl, and the like.

The term "alkylamino" means an alkyl group, as defined above, of thesize indicated, attached to an amino group. This definition includes thedialkylamino group. Examples include methylamino, ethylamino,dimethylamino, and the like.

The term "alkynyl" is used herein to mean straight or branched carbonchain radicals of the size indicated containing at least onecarbon-to-carbon triple bond. Representative of such radicals areethynyl, n-propynyl, butynyl, 3-ethylhexynyl, n-octynyl,4-methylpentynyl, and the like.

The terms "amino acid" and "dipeptide", as used herein, refer,respectively, to a single α-amino acid or two alpha-amino acids joinedby an amide (peptide) bond. The amino acids may be any of thenaturally-occurring amino acids such as, for example, valine, glycine,norvaline, alanine, glutamic acid, glutamine, aspartic acid, leucine,isoleucine, proline, methionine, phenylalanine, or the like, or they maybe synthetic amino acids such as cyclohexylalanine, for example. Theamino acids may be in the L or D configuration or may be represented bya mixture of the two isomers. If not specified, amino acid substituentsare optically active and have the L configuration.

The term "carbocyclic-C₆ -C₁₀ -aryl" as used herein refers to aromaticradicals having six to ten carbon atoms in a single or fused ringsystem. Representative examples include phenyl, 1-naphthyl, 2-naphthyl,and the like.

The term "carbocyclic C₆ -C₁₀ -aryloxy" means an oxygen atom linked byan ether bond to a carbocyclic-C₆ -C₁₀ -aryl group, as defined above,and exemplified by phenoxy, benzyloxy, and the like.

The term "carbocyclic C₆ -C₁₀ -aryloxyalkyl" means a carbocyclic C₆ -C₁₀-aryloxy group, as defined above, attached to an alkyl group, as definedabove.

The term "carbocyclic arylalkyl" means an alkyl group, as defined above,of the size indicated substituted with a carbocyclic-C₆ -C₁₀ -arylgroup, as defined above. Representative examples of carbocyclic-C₆ -C₁₀-arylalkyl groups are benzyl and phenylethyl groups.

The term "catechol-protecting groups" as used herein refers to groupsused to derivatize catechol hydroxyl oxygen atoms in order to preventundesired reactions or degradation during a synthesis. The term"protecting group" is well known in the art and refers to substituentson functional groups of compounds undergoing chemical transformationwhich prevent undesired reactions and degradations during a synthesis;see, for example, T. H. Greene, Protective Groups in Organic Synthesis,John Wiley & Sons, New York (1981). These derivatizing groups may beselected from phenol-protecting groups or they may be selected fromthose groups which are particularly suitable for the protection ofcatechols because of the proximity of the two hydroxyl functions on thecatechol ring. Commonly used catechol-protecting groups include dimethylethers, dibenzyl ethers, cyclohexylidene ketals, methylene acetals,acetonide derivatives, diphenylmethylene ketals, cyclic borate esters,cyclic carbonate esters, cyclic carbamates and the like.

The term "cycloalkyl" as used herein refers to a C₃ -and-up monocyclic,C₄ -and-up bicyclic or C₅ -and-up tricyclic cyclic group, of the sizeindicated, that are fully saturated or partially unsaturated, such ascyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclohexene,cycloheptane, cycloheptene, cyclooctane, cyclooctene, cycloctadiene,bicycloheptane, bicyclooctane, adamantane, norbornane, norbornene,camphene, pinene, and the like.

The term "cycloalkyl-alkyl" means a cycloalkyl group of the sizeindicated attached to an alkyl of the size indicated, for examplecyclo-C₃ -C₈ -alkyl-C₁ -C₁₀ -alkyl.

The term "fused" is used herein to mean two cyclic groups having atleast two atoms in common to both rings.

The term "haloalkyl" refers to a alkyl group of the size indicated, asdefined below, bearing at least one halogen substituent, for examplechloroethyl and trifluoromethyl.

The terms "halo" or "halogen" refer to bromo, chloro, fluoro and iodo.

The term "Het" refers to a three- to twelve-atom monocyclic or four- totwelve-atom bicyclic ring containing one-to-three heteroatomsindependently selected from N, O and S, with the remaining atoms beingcarbon. In the 3- or 4-membered rings, there may be only onehetero-atom, selected from N, O, and S. In the 5- or 6-membered ringsthere may be from 1 to 3 nitrogen atoms, one N and one S, or one N andone O. Examples of Het include furan, tetrahydrofuran, thiophene,pyrrolidine, pyridine, piperidine, isoxazole, indole, quinoline,isoquinoline, tetrahydroisoquinoline, benzofuran and the like.

The term "Het-alkyl" means a Het, as defined above, attached to an alkylof the size indicated, for example, Het-C₁ -C₅ -alkyl.

The term "readily-cleavable group" is used herein to mean substituentswhich are rapidly cleaved in vivo, for example, by hydrolysis in blood,to yield the parent compounds of formula I. Readily-cleavable groupsinclude those substituents commonly referred to as "prodrug moieties".T. Higuchi and V. Stella provide a thorough discussion of the prodrugconcept in Pro-drugs as Novel Delivery Systems, Vol 14 of the A.C.S.Symposium Series, American Chemical Society (1975). Examples ofreadily-cleavable groups include acetyl, trimethylacetyl, butanoyl,methyl succinoyl, t-butyl succinoyl, ethoxycarbonyl, methoxycarbonyl,benzoyl, 3-aminocyclohexylidenyl, and the like.

The term "spirocycloalkyl" means a cycloalkyl ring, as defined above, ofthe size indicated bonded to another ring in such a way that a singlecarbon atom is common to both rings.

The term "substituted alkenyl" means an alkenyl group, as defined above,mono-substituted with cyclo-C₃ -C₈ -alkyl, carbocyclic C₆ -C₁₀ -aryl,amino, hydroxy, C₁ -C₄ -alkoxy or with a pyrrolidine, piperidine,pyridine, quinoline, isoquinoline, thiophene or isoxazole heterocycle.

The term "substituted alkoxy" means an oxygen atom linked by an etherbond to a substituted alkyl group, as defined below, of the sizeindicated.

The term "substituted alkyl", as used herein, refers to an alkyl group,as defined above, of the size indicated, that may be mono- orindependently di-substituted with a group selected from selected fromhalogen, hydroxy, C₁ -C₄ -alkoxy, amino, C₁ -C₄ -alkyl amino, C₃ -C₈-cycloalkyl and C₁ -C₄ -alkanoylamino.

The term "substituted alkylamino" means a substituted alkyl group, asdefined above, of the size indicated, attached to an amine group.

The term "substituted alkynyl" means an alkynyl group mono-substitutedwith cyclo-C₃ -C₈ -alkyl, carbocyclic C₆ -C₁₀ -aryl, or with a Het asdefined below.

The term "substituted carbocyclic-C₆ -C₁₀ -aryl" means a carbocyclic-C₆-C₁₀ -aryl group, as defined above, substituted with 1-5 non-hydrogensubstituents, for example, halogen, hydroxy, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, or one phenyl group or one trifluoromethyl group in conjunctionwith 0-to-4 of the said non-hydrogen substituents.

The term "substituted carbocyclic-C₆ -C₁₀ -arylalkyl" means asubstituted carbocyclic-C₆ -C₁₀ -aryl, as defined above, attached to analkyl group, as defined above, of the size indicated.

The term "substituted carbocyclic-C₆ -C₁₀ -aryloxy" means an oxygen atomlinked by an ether bond to a substituted carbocyclic C₆ -C₁₀ -arylgroup, as defined above.

The term "substituted carbocyclic C₆ -C₁₀ -aryloxyalkyl" means asubstituted carbocyclic C₆ -C₁₀ -aryloxy group, as defined above,attached to an alkyl group, as defined above.

The term "substituted cycloalkyl" means a cycloalkyl group, as definedabove, of the size indicated, that may be mono- or di-substituted with agroup selected from halogen, hydroxy, C₁ -C₄ -alkoxy, amino, C₁ -C₄-alkyl amino, and C₁ -C₄ -alkanoylamino.

The term "substituted Het" refers to a Het, as defined above, that maypossess 1 to 3 substituents selected from halogen, hydroxy, C₁ -C₄-alkoxy, amino, C₁ -C₄ -alkyl amino, and C₁ -C₄ -alkanoylamino.

The term "substituted Het-alkyl" means a Het-alkyl group, as definedabove, that may possess 1 to 3 substituents selected from halogen,hydroxy, C₁ -C₁₀ -alkoxy, amino, C₁ -C₄ -alkyl amino, and C₁ -C₄-alkanoylamino.

The term "administration" of the dopaminergic agent or composition, asused herein, refers to systemic use as when taken orally, parenterally,by inhalation spray, by nasal, rectal or buccal routes, or topically indosage form unit formulations containing conventional nontoxicpharmaceutically acceptable carriers, adjuvants and vehicles as desired.

The term "parenteral" as used herein includes intravenous,intramuscular, intraperitoneal, intrasternal, subcutaneous andintraarticular injection and infusion techniques.

By "pharmaceutically acceptable" it is meant those salts, amides andesters which are, within the scope of sound medical judgement, suitablefor use in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio, effective for theirintended use in the treatment of psychological, neurological,cardiovascular and addictive behavior disorders. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds offormula I, or separately by reacting the free base function with asuitable organic acid. Representative acid addition salts includehydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate,valerate, oleate, palmitate, stearate, laurate, borate, benzoate,lactate, phosphate, toluenesulfonate, methanesulfonate, citrate,maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate,lactobionate, lauryl sulfate salts and the like. Representative alkalior alkaline earth metal salts include sodium, calcium, potassium,magnesium salts and the like. Examples of pharmaceutically acceptable,nontoxic amides of the compounds of formula I include amides derivedfrom C₁ -C₆ -alkyl carboxylic acids wherein the alkyl groups arestraight or branched chain, aromatic carboxylic acids such asderivatives of benzoic acid and heterocyclic carboxylic acids such asfuran-2-carboxylic acid or nicotinic acid. Amides of the compounds offormula I may be prepared according to conventional methods. It isunderstood that amides of the compounds of the present invention includeamino acid and polypeptide derivatives of the amines of formula I.

As used herein, the term "pharmaceutically acceptable carriers" means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of the materials that can serve as pharmaceutically acceptablecarders are sugars, such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols such as glycerin, sorbitol, mannitoland polyethylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol and phosphate buffer solutions, as well as othernon-toxic compatible substances used in pharmaceutical formulations.Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfateand magnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgement of the formulator. Examples ofpharmaceutically acceptable antioxidants include water solubleantioxidants such as ascorbic acid, cysteine hydrochloride, sodiumbisulfite, sodium metabisulfite, sodium sulfite, and the like; oilsoluble antioxidants such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol and the like; and the metal chelating agentssuch as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid and the like.

By a "therapeutically effective amount" of the dopaminergic agent ismeant a sufficient amount of the compound to treat dopamine-relateddisorders at a reasonable benefit/risk ratio applicable to any medicaltreatment. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgement.The specific therapeutically effective dose level for any particularpatient will depend upon a variety of factors including the disorderbeing treated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidently with the specific compound employed; andlike factors well known in the medical arts.

The term "affective disorder" as used herein refers to disorders thatare characterized by changes in mood as the primary clinicalmanifestation, for example, depression.

The term "antipsychotic agent" as used herein refers to drugs usedextensively in the symptomatic management of all forms of schizophrenia,organic psychosis, the manic phase of manic depressive illness and otheracute idiopathic illnesses and occasionally used in depression or insevere anxiety.

The term "attention deficit disorder" refers to a recently classifiedpediatric neuropsychiatric disorder characterized by inattention,impulsivity, distractibility and sometimes hyperactivity, which replacesthe less formal diagnoses of hyperactivity syndrome, hyperkineticsyndrome, minimal brain dysfunction and specific learning disability.The disorder is prevalent among pre-adolescent children and is reflectedin poor school performance and social behavior and has been described inexperimental reports of impaired perceptual, cognitive and motorfunction.

The term "cognitive impairment" refers to a deficiency in any of theaspects of the cognitive (information processing) functions ofperceiving, thinking and remembering.

The term "dopamine-related cardiovascular disorders" as used hereinrefers to conditions which can be reversed or improved by administrationof dopamine or a dopaminergic agent, either alone or in combinationtherapy with other classes of cardiovascular agents. The usefulness ofdopaminergic agents in cardiovascular diseases, for example in thetreatment of shock and congestive heart failure, is based on the known,but incompletely understood, role of dopamine in the cardiovascularsystem, especially the effects of dopamine on the heart and the abilityof dopamine to produce vasoconstriction while maintaining blood flowthrough renal and mesenteric beds. Also included are other related,potential uses for dopaminergic agents which, because the role ofdopamine in the cardiovascular system is presently incompletely defined,are still under investigation, for example use in renal failure.

The term "dopamine-related neurological and psychological disorders" asused herein refers to behavioral disorders, such as psychoses andaddictive behavior disorders; affective disorders, such as majordepression; and movement disorders such as Parkinson's Disease,Huntington's Disease and Gilles de la Tourette's syndrome; which havebeen linked, pharmacologically and/or clinically, to either insufficientor excessive functional dopaminergic activity in the CNS. Also includedare miscellaneous indications for which dopaminergic agents have beenfound to be clinically useful. Examples of such indications aredisorders characterized by vomiting, such as uremia, gastroenteritis,carcinomatosis, radiation sickness, and emesis caused by a variety ofdrugs; intractable hiccough and alcoholic hallucinosis.

"Normal dopamine levels" are those levels of dopamine that are found inthe brains of control subjects and are usually measured as levels of thedopamine metabolites homovanillic acid (3-methoxy-4-hydroxyphenylaceticacid) and 3,4-dihydroxyphenylacetic acid. Abnormal dopamine levels arethose levels that are not within the range of dopamine levels found inthe brains of control subjects.

The term "substance abuse" is used herein to mean periodic or continuedself-administration of psychoactive substances in the absence of medicalindications and despite the presence of persistent or recurrent social,occupational, psychological or physical problems that the person knowsare caused by or may be exacerbated by continued use of the substance.

The total daily dose of the compounds of this invention administered toa host in single or in divided doses can be in amounts, for example,from 0.01 to 25 mg/kg body weight or more usually from 0.1 to 15 mg/kgbody weight. Single dose compositions may contain such amounts orsubmultiples thereof to make up the daily dose. In general, treatmentregimens according to the present invention comprise administration to apatient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in multiple doses or in asingle dose of from 10 mg to 1000 mg.

The compounds of the present invention may be administered alone or incombination or in concurrent therapy with other agents which effect thedopaminergic system such as L-dopa, amantadine, apomorphine orbromocryptine; and with cholinergic agents, for example, benztropine,biperiden, ethopromazine, procyclidine, trihexylphenidyl and the like.The compounds of the present invention may also be co-administered withagents, for example enzyme inhibitors, which block their metabolictransformation outside the CNS.

This invention also provides pharmaceutical compositions in unit dosageforms, comprising a therapeutically effective amount of a compound (orcompounds) of this invention in combination with a conventionalpharmaceutical carrier.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulation can be sterilized, for example, by filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium justprior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of a drug from subcutaneous or intramuscular injection.The most common way to accomplish this is to inject a suspension ofcrystalline or amorphous material with poor water solubility The rate ofabsorption of the drug becomes dependent on the rate of dissolution ofthe drug which is, in turn, dependent on the physical state of the drug,for example, the crystal size and the crystalline form. Another approachto delaying absorption of a drug is to administer the drug as a solutionor suspension in oil. Injectable depot forms can also be made by formingmicrocapsule matrices of drugs and biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer andthe composition of the polymer, the rate of drug release can becontrolled. Examples of other biodegradable polymers includepoly-orthoesters and polyanhydrides. The depot injectables can also bemade by entrapping the drug in liposomes or microemulsions which arecompatible with body tissues.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycol which are solid at ordinary temperaturebut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, prills and granules. In such solid dosage formsthe active compound may be admixed with at least one inert diluent suchas sucrose, lactose or starch. Such dosage forms may also comprise, asis normal practice, additional substances other than inert diluents,e.g., tableting lubricants and other tableting aids such as magnesiumstearate and microcrystalline cellulose. In the case of capsules,tablets and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings andother release-controlling coatings.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such exipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable lo emulsions, microemulsions, solutions, suspensions, syrupsand elixirs containing inert diluents commonly used in the art such aswater. Such compositions may also comprise adjuvants, such as wettingagents; emulsifying and suspending agents; sweetening, flavoring andperfuming agents.

If desired, the compounds of the present invention can be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes and microspheres. They may be sterilized, for example, byfiltration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which candissolve in sterile water, or some other sterile injectable mediumimmediately before use.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may optionally contain opacifyingagents and can also be of a composition that they release the activeingredient(s) only, or preferably, in a certain part of the intestinaltract, optionally in a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention further include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulations, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispersing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

In general, the compounds of this invention are synthesized by reactionschemes I through XVI as illustrated below. It should be understood thatR¹ -R⁷ as used herein correspond to the R groups identified by formulaI. The oxygens of the catechol groups can be derivatized with"protecting groups" or "leaving groups" which are known in the art andcan be prepared by conventional methods. These derivatizing groups canbe selected from among phenol derivatives and derivatives which aresuitable to catechols because of the proximity of the two hydroxylfunctions. Commonly used phenol derivatives are ethers, for examplealkyl, alkenyl, and cycloalkyl ethers (such as methyl, isopropyl,t-butyl, cyclopropylmethyl, cyclohexyl, allyl ethers and the like);alkoxyalkyl ethers such as methoxymethyl or methoxyethoxymethyl etherand the like; alkylthioalkyl ethers such as methylthiomethyl ether;tetrahydropyranyl ethers, arylalkyl ethers (such as benzyl,o-nitrobenzyl, 9-anthrylmethyl, 4-picolyl ethers and the like);trialkylsilyl ethers such as trimethylsilyl, triethylsilyl,t-butyldimethylsilyl ethers and the like; alkyl esters such as acetates,propionates, n-butyrates, isobutyrates, trimethylacetates, benzoates andthe like; substituted alkyl esters such as3-(methoxycarbonyl)propionate, 3-aminopropionate,3-(t-butoxycarbonyl)propionate and the like; carbonates such as methylethyl, 2,2,2-trichloroethyl, vinyl, benzyl and the like; carbamates suchas methyl, isobutyl, phenyl, benzyl, dimethyl, and the like; andsulfonates such as methanesulfonate, trifluoromethanesulfonate,toluenesulfonate and the like. Commonly used catechol derivativesinclude cyclic acetals and ketals such as methylene acetal, acetonidederivatives, cyclohexylidene ketal, diphenylmethylene ketal and thelike; cyclic esters such as borate esters, cyclic carbonate esters andthe like.

The condensation of amino groups (such as those present in the certainof the compounds of this invention) with amino acids and peptides may beeffected in accordance with conventional condensation methods such asthe azide method, the mixed acid anhydride method, the DCC(dicyclohexylcarbodiimide) method, the active ester method(p-nitrophenyl ester method, N-hydroxysuccinic acid imide ester method,cyanomethyl ester method and the like), the Woodward reagent K method,the DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classicalmethods for amino acid condensation reactions are described in "PeptideSynthesis" Second Edition, M. Bodansky, Y. S. Klausner and M. A. Ondetti(1976).

As in conventional peptide synthesis, branched chain amino and carboxylgroups at alpha and omega positions in amino acids may be protected anddeprotected if necessary. The protecting groups for amino groups whichcan be used involve, for example, benzyloxycarbonyl (Z),o-chloro-benzyloxycarbonyl ((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z(NO2)),p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc),t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl, adamantyloxycarbonyl(Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl (Bpoc),9-fluorenylmethoxycarbonyl (Fmoc), methylsulfonylethoxy carbonyl (Msc),trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (Nps),diphenylphosphinothioyl (Ppt) and dimethylphosphinothioyl (Mpt).

The examples of protecting groups for carboxyl groups involve, forexample, benzyl ester (OBn), cyclohexyl ester, 4-nitrobenzyl ester(OBnNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and thelike.

In the course of the synthesis of certain of the compounds of thepresent invention, specific amino acids having functional groups otherthan amino and carboxyl groups in the branched chain such as arginine,cysteine, serine and the like may be protected, if necessary, withsuitable protecting groups. It is preferable that, for example, theguanidino group (N^(G)) in arginine may be protected with nitro,p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl(Adoc), p-methoxybenzenesulfonyl, 4-methoxy-2,6-dimethylbenzenesulfonyl(Mts) and the like, and the thiol group in cysteine may be protectedwith benzyl, p-methoxybenzyl, triphenylmethyl, acetomidomethyl,ethylcarbamyl, 4-methylbenzyl (4-MeBn, 2,4,6,-trimethylbenzyl (Tmb) andthe like, and the hydroxy group in serine may be protected with benzyl(Bn), t-butyl, acetyl, tetrahydropyranyl (THP) and the like.

SCHEME I A

The compounds of formulae I A and I B are synthesized by the methoddiscussed herein. 2,3-Dihydroxybenzaldehyde (which has the two catecholhydroxy groups protected by, for example, alkyl groups preferably methylgroups) and a substituted acetic acid derivative, such as phenyl aceticacid, are condensed in the presence of a dehydrating agent, such asacetic anhydride, and a proton acceptor such as triethylamine (TEA) togive compound 2. The carboxylic acid (or acid derivative such as themethyl or ethyl ester) of compound 2 is reduced by a reducing agent suchas lithium aluminum hydride (LAH) preferably in an ether solvent such astetrahydrofuran (THF). The leaving group ability of the hydroxyl groupof compound 3 is enhanced by derivatizing it with, for example,methanesulfonyl chloride, in the presence of a proton acceptor such asTEA, and it is then converted to the cyano compound 4 by nucleophilicdisplacement with a salt of cyanic acid such as sodium cyanide in apolar solvent such as dimethyl sulfoxide (DMSO). The cyano group ishydrolyzed to the corresponding carboxylic acid group under basicconditions using, for example, aqueous sodium hydroxide, and thenaphthalenone derivative (compound 5) is prepared by intramolecularacylation of the protected catechol ring using a dehydrating agent suchas polyphosphoric acid or methanesulfonic acid/tri-fluoroacetic acid.Compound 5 is converted to the corresponding cyanohydrin by treatmentwith a nucleophilic cyano derivative such as trimethylsilylcyanide andthe cyano alcohol is reduced to the amine (compound 6) by treatment witha reducing agent such as LAH, preferably in a ether solvent such asdiethyl ether. The 1-hydroxyl group is eliminated from compound 6 byheating it under acidic conditions, e.g. in isopropyl alcohol saturatedwith hydrochloric acid, to produce the dihydronaphthalene derivative(compound 7). Compound I A is produced when the catechol hydroxyl groupsof compound 7 are deprotected with, for example, boron tribromide orboron trichloride in an inert solvent such as dichloroethane ormethylene chloride. Compound 7 is also hydrogenated to the correspondingtetrahydronaphthalene derivative in the presence of a catalyst such aspalladium or platinum on carbon and then deprotected with e.g. borontribromide or boron trichloride to produce IB. In the preferredembodiments of compounds I A and I B, R³ is phenyl or cyclohexyl and Xis bromo or chloro.

SCHEME I B

The compounds of formula I are alternately synthesized by the methoddiscussed herein. 2,3-Dihydroxybenzaldehyde with both the catecholhydroxyl protected as described in Example I and the aldehyde groupderivatized as its dithiane is treated with a base such as n-butyllithium to generate the anion (compound 8), and condensed with analpha-beta unsaturated acid derivative such as ethyl cinnamate in thepresence of dimethyl-2-imidizolidinone to produce compound 9. Thedithiane group is removed from compound 9 by treatment with hydrogen inthe presence of a catalyst such as Raney nickel and convened to compound5 as described in Scheme IA. Compound 5 is further converted to IA andIB as described in Scheme IA.

SCHEME II

The compounds of formulae II A and II B are prepared by the methodillustrated in Scheme II. The naphthalenones of formula 5 are treatedsequentially with a suitable base such as lithiumbis(trimethylsilyl)amide and a haloacetic acid ester, for example ethylbromoacetate, to afford the compounds of formula 10. Compounds offormula 10 are converted to compounds of formula 11 by treatment withdiethylaluminum cyanide under anhydrous conditions, followed bycyclization in aqueous mineral acid, for example aqueous hydrochloricacid. Compounds of formula 11 are reduced using a suitable reagent suchas LAH followed by elimination with an acid such as hydrogen chloride inisopropanol to afford compounds of formula 12. Compounds of formula 12are treated with a suitable reagent for removal of the catecholprotecting groups, for example boron tribromide, to yield the compoundsof formula II A.

Alternately, compounds of formula 11 are converted to compounds offormula 13 by treatment with a mineral acid in anhydrous alcohol. Thecompounds of formula 13 are, in turn, converted to compounds of formula14 by treatment with magnesium followed by aqueous mineral acid andreduction using a suitable reagent such as LAH. The compounds of formula14 are then treated with a suitable reagent for the removal of thecatechol protecting groups, for example boron tribromide to afford thecompounds of formula II B.

SCHEME III

Compounds of formulae III A-III E are synthesized by the methodsillustrated in Scheme III. Naphthalenones of formula 5 are alkylated toafford the compounds of formula 15 by treatment with a suitable base(forexample lithium bis(trimethylsilyl)amide and a suitable alkylating agentsuch as allyl bromide. The compounds of formula 15 are converted to thecompounds of formula 16 by sequential treatment with trimethylsilylcyanide and a suitable reducing agent such as LAH. The compounds offormula 16 are, in turn, cyclized to the compounds of formula 17 bytreatment with a suitably reactive carbonic acid derivative such as1,1'-carbonyldiimidazole.

Compounds of formula Ill A are prepared by reduction of compounds offormula 17 with a suitable reagent (for example by hydrogenation using asuitable catalyst such as palladium on carbon), followed by treatmentwith a suitable reagent for removal of the catechol protecting groupssuch as boron tribromide resulting in simultaneous elimination of carbondioxide to afford the desired amines.

Compounds of formula III B are prepared by hydrogenation of compounds offormula 17 using a suitable catalyst such as palladium hydroxide oncarbon, followed by treatment with a suitable reagent for removal of thecatechol protecting groups such as boron tribromide.

Compounds of formulae III C, III D and III E are prepared from compoundsof formula 20. Compounds of formula 17 are converted to compounds offormula 20 by hydroboration/oxidation under standard conditions.Compounds of formula 20 are converted to compounds of formula III C bytreatment with 3 equivalents of boron tribromide. Compounds of formula20 are converted to compounds of formula HI D by treatment with 4.5equivalents of boron tribromide. Compounds of formula 20 are convertedto compounds of formula III E by reductive opening of the oxazolidinonering followed by treatment with a suitable reagent for removal of thecatechol protecting groups such as boron tribromide.

SCHEME IV

The compounds of formula IV A, IV B and IV C are synthesized by themethod discussed herein. A catechol (compound 22 wherein R¹ is selectedfrom alkyl groups such as methyl or both R¹ groups together form a spirocycloalkyl group such as cyclohexyl) is reacted in the presence of abase, such as n-butyl lithium, with an epoxide such as compound 23(wherein R⁴ is hydrogen and R³ is preferably selected from cyclohexyl,phenyl, ethyl, p-methoxyphenoxymethyl, phenoxymethyl,o-phenylphenoxymethyl, p-t-butylphenoxymethyl, p-bromophenoxymethyl,adamantyl, benzyl, phenylethyl, n-octyl, n-hexyl, 1-hex-5-enyl, n-decyl,t-butyl or benzyloxymethyl; or R³ and R⁴ together form a spirocycloalkylgroup, such as cyclohexyl), to produce compound 24.

Compound 24 can be oxidized to the corresponding ketone with anoxidizing agent such as pyridinium chlorochromate (PCC) and theresultant ketone can be stereoselectively reduced with, for example,B-chlorodiisopinocampheylborane (as described in Example 46) to give theoptically active isomers of compound 24.

Compound 24 is condensed with a bromoaldehyde such as bromoacetaldehydedimethyl acetal or 3-bromopropionaldehyde dimethyl acetal to form thesubstituted benzopyran derivative 26. Compound 26 is converted tocompound 27 by treatment with a nucleophilic azide such as lithium azidein a polar solvent such as dimethyl formamide, followed by reduction ofthe azido compound, for example with LAH. Compound 27 is converted to IVA by generation of the amine salt in acidic solution and deprotection ofthe catechol hydroxyl groups in acid solution. Compound 27 is convertedto compound IV B by treatment with ethyl formate followed by reductionwith, for example LAH and generation of the amine salt with deprotectionof the catechol hydroxyl groups in acidic solution. Compound 26 isconverted to IV C by treatment with an amine such as allyl amine,cyclopropylamine or pyrrolidine, followed by deprotection of thecatechol hydroxyl groups and generation of the amine salt in acidicsolution. In the case wherein the epoxide 23 is substituted with abenzyloxymethyl group (i.e. R³ =benzyloxymethyl), R³ is furtherelaborated as shown in Scheme V.

SCHEME V

The compounds of formula V A, V B, V C, V D and V E are synthesized bythe methods illustrated in Scheme V. R¹ is defined in Scheme IV.Compound of formula 28 are alkylated with an epoxide of formula 29(wherein Bn is benzyl, z is an integer from 0 to 6, and R¹² is asubstituent selected from the group R³) to afford compounds of formula30. Compounds of formula 30 are condensed withN-formylamino-acetaldehyde dimethyl acetal in the presence of a catalystselected from boron trifluoride etherate, zinc triflate, trimethylsilyltriflate, methanesulfonic acid, p-toluenesulfonic acid andpolyphosphoric acid to afford the isochromans of formula 31. The formylgroup is removed and replaced with a t-butyloxycarbonyl protecting groupand the hydroxy group is deprotected preferably by hydrogenolysis toafford the compounds of formula 32.

Compounds of formula V A are prepared by removal of the amino andcatechol protecting groups from the compounds of formula 32 in acidicsolution. Compounds of formula V B are prepared from the compounds offormula 32 by the following sequence of reactions: activation of thehydroxymethyl group, for example by reaction with methanesulfonylchloride; displacement with a nucleophilic azide such as lithium azideto give the azidomethyl compound; followed by reduction of the azidogroup to give the compounds of formula 33 and deprotection of the amineand the catechol hydroxyls with an acid such as hydrochloric acid inalcohol.

Compounds of formula V C are prepared from the compounds of formula 33by acylation of the free amino group followed by simultaneous removal ofthe amine and catechol protecting groups in acidic solution.

Alternately, compounds of formula 31 are converted to compounds offormula 34 by hydrogenolysis followed by activation of the hydroxymethylgroup, for example by reaction with methanesulfonyl chloride anddisplacement with a nucleophilic azide such as lithium azide. Thecompounds of formula 34 are, in turn, converted to compounds of formulaV D by reduction of the formyl group and the azido group followed byremoval of the catechol protecting groups in acidic solution. Thecompounds of formula 34 are also converted to the compounds of formula VE by reduction of the azido group, formylation of the free amino,simultaneous reduction of both formyl groups to methylamino groups andtreatment with a suitable reagent for the removal of the catecholprotecting groups.

Alternately, compounds of formula 32 are converted to compounds offormula V F by activation of the 3-hydroxymethyl group, for example byreaction with methanesulfonyl chloride followed by displacement with anucleophilic amine, NHR⁹ R¹⁰, in which R⁹ and R¹⁰ are independentlyselected from H and lower alkyl or R⁹ and R¹⁰ together form a ringcontaining a nitrogen atom such as pyrrolinyl or piperidinyl ormorpholino, followed by deprotection of the amino group and the catecholhydroxyls in acidic solution.

SCHEME VI

According to reaction Scheme VI A, compounds of formula 35, wherein R1is as defined in Scheme IV, are converted to compounds of formula 36 bytreatment with oxalyl chloride followed by treatment with O-methylN-methyl hydroxylamine. Compounds of formula 36 reacted with furan inthe presence of a suitable base such as n-butyl lithium to afford thecompounds of formula 37. The furan ring and the ketone are then reduced,for example by hydrogenation using a suitable catalyst such as palladiumon carbon to afford the compounds of formula 24. Compounds of formula 24are valuable intermediates and can be converted to the isochroman andisothiochroman compounds of the present invention by any of the methodsshown in Schemes IV, V, VII and VIII.

Chiral compounds may be prepared according to Scheme VI B, whereincompounds of formula 22, wherein R1 is as defined in Scheme IV, areconverted into compounds of formula 38 by treatment with a strong base,such as n-butyl lithium, followed by reaction with chiralepichlorohydrin. The chiral compounds of formula 38 are converted intothe chiral epoxides of formula 38A by treatment with a strong base, suchas NaOH or KOH in a polar organic solvent, such as a mixture of etherand alcohol. The chiral 38A is then reacted with an organometalliccompound, for example, an alkyl magnesium halide, an organocuprate or alithium acetylide, for example, in a non-polar organic solvent, toprepare the chiral alcohol of formula 38B. The compound 38B is reactedwith N-formylaminoacetaldehyde dimethyl acetal in the presence of anacid catalyst as described in Scheme XVIA below, followed by hydrolysisof the formyl group to give chiral compounds of formula 39. Compounds offormula 39 can be either hydrolyzed or reduced followed by conversion tothe HCl salt to give certain chiral compounds of formula VIB directly.Alternately, the formyl group can be replaced with an amino protectinggroup and the intermediate further modified to give other compounds offormula I, for example as illustrated in Scheme V above.

SCHEME VIIA

Compounds of formulae 43 or 44, where either X or Y is Br or Cl, aresynthesized by the method illustrated in in Scheme VIIA. Compounds offormula IVA are protected at the amino position with a suitableN-protecting group, such as BOC, AOC, or ADOC, for example, by reactionwith the appropriate reagent, to give the compounds of formula 42. Thesecompounds are then reacted with a brominating or chlorinating reagent,such as free bromine or chlorine, HOCl, HOBr, N-bromosuccinimide, orN-chlorosuccinimide, for example, and the protecting group is removed byhydrolysis with the appropriate reagent. A mixture of compounds 43 and44 is obtained, which may be separated by standard procedures in theart.

SCHEME VIIB

Compounds of formula 46, where either X or Y is fluoro, methyl or ethylare synthesized by the procedure outlined in Scheme VIIB. The compounds45, analogous to the compounds of formula 22 of Scheme IV, are reactedaccording to the procedures given in Scheme IV, in order to prepare thedesired compounds of formula 46, where X or Y is fluoro, methyl, orethyl. These compounds may be taken further to prepare the compoundswhere the nitrogen is substituted, as illustrated in Schemes IV or IX.

SCHEME VIII

The compounds of formula VIII are synthesized by the methods illustratedin Scheme VIII. Intermediates of formula 24 are converted to thecorresponding thio compounds of formula 40 by treatment withtriphenylphosphine and diisopropylazodicarboxylate, followed bytreatment with thioacetic acid to afford an intermediate thiolacetatewhich was treated with a suitable reagent such as LAH. The compounds offormula 40 are valuable intermediates and are convened to the compoundsof formula VIII and the thio equivalents of compounds IV, V, VI and VIIby the methods illustrated in Schemes IV-VII.

SCHEME IX

The compounds of formula IX A and IX B are synthesized by the methoddiscussed herein. R¹, R² and R³ are defined in Scheme I. Compound 5 isconverted to the cyanohydrin by treatment with a nucleophilic cyanoderivative such as trimethylsilyl cyanide in the presence of a catalystsuch as aluminum trichloride. The cyanohydrin is dehydrated to thea,b-unsaturated nitrile by treatment with a dehydrating agent such asTFA/p-toluenesulfonic acid and the unsaturated nitrile reduced to thesaturated nitrile (compound 46) by treatment with a reducing agent suchas sodium borohydride. The nitrile group is hydrolyzed to a carboxylicacid group (compound 47) and the acid converted to theN-methoxy-N-methyl amide 48 by sequential treatment with an activatingagent, such as oxalyl chloride, to generate the acid chloride, andN-methoxymethylamine. Compound 48 is converted to a mixture of thediastereomeric pyrrolidinyl derivatives 49 and 50 by treatment with2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesiumbromide (by the procedure given in Tetrahedron Letters 25:5271-5274(1984)) followed by reduction with a reducing agent such as sodiumborohydride, and the diastereomers are separated chromatographically.The separated isomers 49 and 50 are convened to IX A and IX B,respectively, by treatment with boron trihalide, preferably borontribromide.

SCHEME X

The compounds X A and X B are synthesized by the method discussedherein. R¹ -R³ are defined in Scheme I. Compound 5 is converted tocompound 51 by treatment with dimethyl succinate in the presence of abase such as potassium t-butoxide. Compound 51 is reduced to thecorresponding 1,2,3,4-tetrahydronaph-thalene and the tricyclic ringsystem is formed by treating compound 51, with a dehydrating agent suchas polyphosphoric acid. Four isomeric products are obtained. Two of theisomers, compounds 52 and 53, are carried on to X A and X B,respectively. Reduction of the 3-keto group of compounds 52 and 53 with,for example hydrogen in the presence of a catalyst such as palladium oncarbon support is followed by hydrolysis of the ester in basic solutionto give compounds 54 and 55, respectively. Compounds 54 and 55 are eachtreated with diphenylphosphoryl azide and benzyl alcohol in the presenceof a base such as triethylamine to give the carbobenzyloxy protectedamino derivatives, which are deprotected by hydrogenolysis using, forexample, palladium on carbon support as a catalyst, and demethylationusing, for example,. boron tribromide to give X A and X B.

SCHEME XI

The compounds of formula XI are synthesized by the method describedherein. R¹ -R³ are defined in Scheme I. Compound 5 is convened to theα-bromoketone by treatment with a brominating agent such asphenyltrimethylammonium tribromide. The bromide undergoes nucleophilicdisplacement, for example, with the anion of thiophenol to give theα-thiophenylketone compound 56. The ketone is reduced to the alcoholwith a reducing agent such as sodium borohydride and the hydroxy groupis eliminated with a dehydrating agent such as p-toluenesulfonic acid togive the thio-enolether. The sulfur atom of the thio-enolether isoxidized to the sulfoxide with an oxidizing agent such as mCPBA to givecompound 57. The amine component is made by a nucleophilic displacementon chloromethyltrimethylsilane by an amine (compound 58), such asbenzylamine. The imine is formed by treatment of the amine with analdehyde such as formaldehyde and then an alcohol, such as methanol, isadded to form the alkoxymethyl amine compound 60. Compound 60 is thenreacted with the sulfoxide (compound 57) in the presence of an acid,such as TFA to generate the azomethine ylid in situ which traps theactivated double bond of the: a, b-unsaturated sulfoxide to give a1,3-dipolar addition adduct which, on heating, spontaneously undergoeselimination to give the cyclization/elimination product, compound 61.The nitrogen can be deprotected by treatment with an acylating agent,such as 1-chloroethylchloroformate followed by acyl group removal with anucleophile, such as methanol to give: compound 62. The catechol isdeprotected by treatment with a boron trihalide, preferably borontribromide to give XI.

SCHEME XII

The compounds of formulae XII A, XII B and XII C are synthesized by themethods described herein. R¹ and R³ are defined in Scheme I. Compoundsof the formula 12 are reduced by catalytic hydrogenation using asuitable catalyst such as palladium hydroxide to afford the compounds offormula 63. The compounds of formula 63 are treated with a suitablereagent for protecting the amino group, for example benzyloxycarbonylchloride, followed by a suitable reagent for activating the hydroxylgroup such as methanesulfonyl chloride to afford the compounds offormula 64. The compounds of formula 64 are, in turn, cyclized bytreatment with a suitable base for example sodium hydride in DMF anddeprotected with acid, for example by treatment with hydrogen bromide inacetic acid, to afford the compounds of formula XII B.

Alternately, the compounds of formula 12 are converted to the compoundsof formula 65 by treatment with a suitable reagent for protecting theamino group, for example benzyloxycarbonyl chloride, followed by asuitable reagent for activating the hydroxyl group such asmethanesulfonyl chloride to afford the compounds of formula 65. Thecompounds of formula 65 are, in turn, cyclized by treatment with asuitable base for example sodium hydride in DMF and deprotected withacid, for example by treatment with hydrogen bromide in acetic acid, toafford the compounds of formula XII A.

The compounds of formula 11 are treated with a suitable reducing agentsuch as LAH to afford the compounds of formula 66. The compounds offormula 66 are treated with an appropriately reactive carbonic acidderivative, for example carbonyl diimidazole to afford theoxazolidinones of formula 67. The compounds of formula 67 are reduced bycatalytic hydrogenation using a suitable catalyst such as palladiumhydroxide to afford the compounds of formula 68. The compounds offormula 68 are treated with a suitable reagent for protecting the aminogroup, for example benzyloxycarbonyl chloride, followed by a suitablereagent for activating the hydroxyl group such as methanesulfonylchloride to afford the compounds of formula 69. The compounds of formula69 are, in turn, cyclized by treatment with a suitable base for examplesodium hydride in DMF and deprotected with acid, for example bytreatment with hydrogen bromide in acetic acid, to afford the compoundsof formula XII C.

SCHEME XIII

The compounds of formulae XIII A and XIII B are synthesized by themethods described herein. R¹ and R³ are defined in Scheme I. Thecompounds of formula 20 are treated with a suitable acid such ashydrogen chloride in a suitable solvent, for example isopropyl alcoholor ethyl alcohol or diethyl ether, in order to open the oxazolidinonering with the elimination of carbon dioxide. The resultant aminoalcohols are treated with a suitable reagent for protecting the aminogroup, for example benzyloxycarbonyl chloride, followed by a suitablereagent for activating the hydroxyl group such as methanesulfonylchloride to afford the compounds of formula 70. The compounds of formula70 are, in rum, cyclized by treatment with a suitable base for examplesodium hydride in DMF and deprotected with acid, for example bytreatment with hydrogen bromide in acetic acid, to afford the compoundsof formula XIII A.

The compounds of formula 21 are treated with a suitable reagent forprotecting the amino group, for example benzyloxycarbonyl chloride,followed by a suitable reagent for lo activating the hydroxyl group suchas methanesulfonyl chloride to afford the compounds of formula 71. Thecompounds of formula 71 are, in turn, cyclized by treatment with asuitable base for example sodium hydride in DMF and deprotected withacid, for example by treatment with hydrogen bromide in acetic acid, toafford the compounds of formula XIII B.

SCHEME XIV

The compounds of formulae XIV A and XIV B are synthesized by the methodsdescribed herein. Compounds of formula 5 are converted to compounds offormula 72 by treatment with dimethyl malonate in the presence of a basesuch as potassium t-butoxide. The tricyclic ring system is formed bytreating a compound of formula 72, with an acid such as polyphosphoricacid, followed by reduction of the keto group with, for example,triethylsilane in trifluoroacetic acid to afford a compound of formula73. Hydrolysis of the ester group in basic solution affords compounds offormula 74. Compounds of formula 74 are treated with diphenylphosphorylazide and benzyl alcohol in the presence of a base such as triethylamineto give the carbobenzyloxy protected amino derivatives, which aredeprotected along with the catechol hydroxyl groups using, for example,hydrogen bromide in acetic acid to give XIV A.

Alternately the compounds of formula 72 are reduced by catalytichydrogenation using a suitable catalyst such as palladium hydroxide toafford the compounds of formula 75. The compounds of formula 75 are, inturn, converted to the compounds of formula XIV B by the same series ofchemical tranformations described above for the conversion of compoundsof formula 72 to compounds of formula XIV A.

SCHEME XV

The compounds of formulae XV A and XV B are synthesized by the methodsdescribed herein. R¹ and R³ are defined in Scheme I. The compounds offormula 5 are converted to compounds of formula 51 by treatment withdimethyl succinate in the presence of a base such as potassiumt-butoxide. The compounds of formula 51 are, in turn, treated with asuitable reducing agent for reducing the acid, for example borane, toafford the corresponding hydroxy compounds of formula 78. The compoundsof formula 78 are treated with a suitable reagent to activate thehydroxyl group, for example methanesulfonyl chloride, followed bydisplacement with a nucleophic cyano derivative such as sodium cyanideto afford the compounds of formula 79. The tricyclic ring structure isformed by an intramolecular Houben-Hoesch reaction using hydrogenchloride and zinc dichloride to give the compounds of formula 80.Reduction of the keto group using, for example, triethylsilane intrifluoroacetic acid, followed by hydrolysis of the ester group in basicsolution affords compounds of formula 81. Compounds of formula 81 aretreated with diphenylphosphoryl azide and benzyl alcohol in the presenceof a base such as triethylamine to give the carbobenzyloxy protectedamino derivatives, which are deprotected along with the catecholhydroxyls using, for example, hydrogen bromide in acetic acid, to giveXV A.

Alternately the compounds of formula 78 are reduced by catalytichydrogenation using a suitable catalyst such as palladium hydroxide toafford the compounds of formula 82. The compounds of formula 82 are, inturn, converted to the compounds of formula XV B by the same series ofchemical tranformations described above for the conversion of compoundsof formula 78 to compounds of formula XIV A.

SCHEME XVIA

The process illustrated in Reaction Scheme XVIA is a novel and practicalmethod for ring closure in the synthesis of the isochroman andthioisochroman compounds of the present invention. Compounds of theformula 24 are condensed with N-formylamino-acetaldehyde dimethyl acetalin the presence of an acid catalyst to afford the compounds of formulaXVIA. The reaction is carried out in an inert solvent, for example achlorinated solvent such as methylene chloride or 1,2-dichloroethane, anether solvent such as diethyl ether or THF, or a polar aprotic solventsuch as acetonitrile. The reaction is carried out in the temperaturerange of from about 0° C. to about 100° C. The preferred reactiontemperature is determined by the choice of solvent, the choice ofcatalyst and the amount of catalyst present. In general, reactions inchlorinated solvents are carded out at lower temperatures than reactionsin more polar solvents and larger amounts of catalyst require lowerreaction temperatures. The formylamino reagent (compounds of formula 86)is present in the reaction mixture at from about 1 to about 4equivalents, preferably from about 1.5 to about 2.0 equivalents. Thecatalyst is preferably selected from boron trifluoride etherate,trimethylsilyl triflate, zinc triflate, polyphosphoric acid,methanesulfonic acid and p-toluene sulfonic acid. The amount of catalystpresent in the reaction mixture depends on the catalyst used, thesolvent and reaction temperature. Generally, the catalyst is present inthe range of from about 1 mole % to about 3 equivalents. Most preferablythe reaction is carded with either 1 mole % trimethylsilyl triflate inrefluxing acetonitrile or with 5 mole % boron trifluoride etherate inrefluxing acetonitrile. The reactions are monitored by TLC analysis todetermine the optimum reaction time for good yields with minimum productdegradation and this time varies with choice of solvent, catalyst andreaction temperature.

The compounds of formula XVI A are valuable intermediates in thesynthesis of the compounds of formula I in which A is an oxygen or asulfur atom (isochromans and thioisochromans). Compounds of formula XVIcan be either hydrolyzed or reduced to give certain compounds of formulaI directly. Alternately, the formyl group can be replaced with an aminoprotecting group and the intermediate further modified to give othercompounds of formula I, for example as illustrated in Scheme V below.Compounds of formula XVI A can be either hydrolyzed or reduced to givecertain compounds of formula I directly.

SCHEME XVIB

The process illustrated in Scheme XVIB is a practical method forpreparing isochroman or thioisochroman compounds substituted withpyrrolidine at the 1-position. The compounds of formula 24 are condensedwith the dimethyl acetal of prolinaldehyde in the presence of an acidcatalyst to afford the compounds of formula XVI B. Chiral or racemicproline aldehyde may be used. The reaction is carded out in an inertsolvent, for example a chlorinated solvent such as methylene chloride or1,2-dichloroethane, an ether solvent such as diethyl ether or THF, or apolar aprotic solvent such as acetonitrile. The reaction is carried outin the temperature range of from about 0° C. to about 100° C. Thepreferred reaction temperature is determined by the choice of solvent,the choice of catalyst and the amount of catalyst present. In general,reactions in chlorinated solvents are carded out at lower temperaturesthan reactions in more polar solvents and larger amounts of catalystrequire lower reaction temperatures. The formylamino reagent (compoundsof formula 86) is present in the reaction mixture at from about 1 toabout 4 equivalents, preferably from about 1.5 to about 2.0 equivalents.The catalyst is preferably selected from boron trifluoride etherate,trimethylsilyl triflate, zinc triflate, polyphosphoric acid,methanesulfonic acid and p-toluene sulfonic acid. The amount of catalystpresent in the reaction mixture depends on the catalyst used, thesolvent and reaction temperature. Generally, the catalyst is present inthe range of from about 1 mole % to about 3 equivalents. Most preferablythe reaction is carried with either 1 mole % trimethylsilyl triflate inrefluxing acetonitrile or with 5 mole % boron trifluoride etherate inrefluxing acetonitrile. The reactions are monitored by TLC analysis todetermine the optimum reaction time for good yields with minimum productdegradation and this time varies with choice of solvent, catalyst andreaction temperature.

The compounds of formula XVI B are valuable intermediates in thesynthesis of the compounds of formula I in which A is an oxygen or asulfur atom (isochromans and thioisochromans).

Scheme XVII

Compounds of formula I, as represented by the compounds of formula XVIIA-D, are alternately synthesized by the methods described herein. Anester compound of formula 86, wherein R³ and R⁴ are as described inScheme IV, is treated with a strong base, preferrably LDA, and reactedwith a bromomethyl catechol derivative of compound 87, wherein R¹ is asdescribed in Scheme I. The intermediate is reduced with a reducing agentsuch as LAH to produce the compound 88.

Compound 88 is selectively oxidized to the aldehyde 89, preferrably byreaction with sulfur trioxide-pyridine, triethylamine and DMSO. Compound89 is reacted with LiTMS-dithiane to form the thiane derivative of thealdehyde. This intermediate is made to undergo an internal ring closureby reacting it with HgCl₂, 5% aqueous methyl cyanide to produce compound90.

The tetralone compound 90 is then converted to the aminomethyl compound91 by reactions described in Scheme I for conversion of compound 5 tocompound 7. Compound 91 may then be converted to the free catecholcompound XVII A as described in Scheme I, or it may be converted tocompound 92, where R⁵ is not hydrogen, as described in Scheme IV, or byadditional alkanoylation followed by reduction to give theamino-disubstituted compounds similar to compounds IVC as described inScheme IV.

Compound 93 is obtained by catalytic reduction as described in Scheme I.

Compounds XVII B, C, and D are obtained by the appropriate deprotectionas described previously.

SCHEME XVIII

Compounds XVIII A-D are synthesized by the methods illustrated in SchemeXVIII. R¹, R³, R⁴ and R⁶ are as described in Scheme XVII. Compounds offormula 90 are converted Scheme XIII into compound 95 by the reactionsdescribed for converting compound 5 into compound 11 in Scheme II. Thelactone 95 is reduced with LAH in THF to produce the amino diol compound96, which by reaction with PBr₃ in methylene chloride undergoes ringclosure to form compound 97. Deprotection of compound 97, by methodsdescribed earlier, produces compound XVIII A.

Alternately, compound 97 may be alkylated at the ring-nitrogen position,by the amino alkylation procedures referred to above, to producecompound 98, which upon deprotection is convened into compound XVIII B.

Also, alternately compound 97 is convened into compound 100 by catalytichydrogenation over a catalyst as described earlier, which may then bedeprotected to give compound XVIII D.

Compound 99 may be formed by the alkylation of compound 100 oralternately by catalytic reduction of compound 98. Deprotection ofcompound 99 produces compound XVIII C. ##STR10##

The foregoing may be better understood by reference to the followingexamples, which are provided for the illustration and not the limitationof the invention.

EXAMPLE 1 5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-oneMethod A Step 1: (E,Z)-3-(2',3'-Dimethoxyphenyl)-2-phenylpropenoic Acid

A solution of 202 g (1.21 mol) of 2,3-dimethoxybenzaldehyde(commercially available from Aldrich Chemical Co.), 200 g (1.47 mol) ofphenyl acetic acid (commercially available from Aldrich Chemical Co.),600 mL of acetic anhydride and 204 mL (1.46 mol) of triethylamine (TEA)was heated at reflux temperature for 24 h. The reaction mixture wasallowed to cool to ambient temperature and 1L of water was added,followed by the addition of 2L of ethyl acetate and another 4L of water.The layers were separated and the organic layer was extracted withsaturated aqueous sodium bicarbonate solution. The combined aqueouslayers were acidified with concentrated hydrochloric acid and extractedwith 4L of ethyl acetate. The ethyl acetate solution was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to give250 g (72% yield) of the title compound as a 30/70 mixture of the E andZ isomers, m.p. 115°-160° C.; DCI MS: 285 (M+H)⁺, 302 (M+NH₄)⁺.

Step 2: 3-(2',3'-Dimethoxyphenyl)-2-phenylpropanol

A solution of 15 g (395 mmol) of lithium aluminum hydride (LAH) in 500mL of tetrahydrofuran (THF) was cooled to 0° C. A solution of(E,Z)-3-(2',3'-dimethoxyphenyl)-2-phenylpropenoic acid (50 g, 176 mmol),from step 1, in 100 mL of THF was added to the LAH solution dropwiseover a 30 min period. The reaction mixture was heated at refluxtemperature for 2 h and then cooled to 0° C. The reaction was quenchedby the sequential addition of 15 mL of water, 15 mL of 15% aqueoussodium hydroxide solution and 45 mL of water. The precipitate wasfiltered and the filtrate concentrated in vacuo to give 46.6 g (97%yield) of the title compound as an oil; ¹ H NMR (CDCl₃) δ: 1.8-0.19 (m,1H), 2.1-2.2 (m, 1H), 2.7-2.95 (m, 1H), 3.0-3.15 (m, 2H), 3.7-3.8 (m,1H), 3.8 (s, 3H), 3.83 (s,3H), 6.63 (d, 1H), 6.75 (d, 1H), 6.9 (t, 1H),7.15-7.4 (m, 5H).

Step 3: 3-(2',3'-Dimethoxyphenyl)-2-phenylpropane 1-methanesulfonate

3-(2',3'-Dimethoxyphenyl)-2-phenylpropanol (41.5 g, 152 mmol), from step2, and 30.5 g (301 mmol) of TEA were dissolved in 300 mL of THF.Methanesulfonyl chloride (34.5 g, 301 mmol) was added slowly to thissolution at 0° C. The reaction mixture was allowed to warm to ambienttemperature. After stirring the reaction mixture for 1 h at ambienttemperature, it was diluted with 300 mL of diethyl ether and washed withwater, dried over anhydrous magnesium sulfate, filtered and concentratedto give 40.8 g (76% yield) of 3-(2',3'-dimethoxyphenyl)-2-phenylpropane1-methanesulfonate as an oil; ¹ H NMR (CDCl₃) δ: 2.7 (s, 3H), 2.96 (dd,1H), 3.1 (dd, 1H), 3.35-3.45 (m, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 4.35(m, 2H), 6.62 (dd, 1H), 6.77 (dd, 1H), 6.9 (t, 1H), 7.2-7.35 (m, 5H).

Step 4: 4-(2',3'-Dimethoxyphenyl)-3-phenylbutanenitrile

3-(2',3'-Dimethoxyphenyl)2-phenylpropane 1-methanesulfonate (40.5 g, 116mmol), from step 3, and 17 g (347 mmol) of sodium cyanide were dissolvedin 100 mL of dimethyl sulfoxide (DMSO) and the resultant solution washeated to 80° C. After being stirred at 80° C. for 18 h, the reactionmixture was allowed to cool to ambient temperature, diluted with ethylacetate and washed sequentially with water and brine. The solvents wereremoved in vacuo to give 25 g (77% yield) of the title compound as anoil; ¹ H NMR (CDCl₃) δ: 2.56 (d, 2H), 3.02 (d, 1H), 3.05 (d, 1H),3.25-3.35 (m, 1H), 3.72 (s, 3H), 3.75 (s, 3H), 6.65 (dd, 1H), 6.8 (dd,1H), 6.93 (t, 1H), 7.2-7.4 (m, 5H).

Step 5: 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric Acid

4-(2',3'-Dimethoxyphenyl)-3-phenylbutanenitrile (20 g, 71 mmol), fromStep 4, was dissolved in 1.5L of ethanol. Sodium hydroxide (20 g, 0.5mol) and 200 mL of water were added and the reaction mixture was heatedat reflux temperature for 24 h. The solvent was removed in vacuo and 1Lof water plus 1L of methylene chloride were added to the residue. Thelayers were separated and the organic layer discarded. The aqueous layerwas acidified with concentrated hydrochloric acid and extracted with 3Lof ethyl acetate. The ethyl acetate solution was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give 21 g (98%yield) of the title compound as an oil; 1H NMR (CDCl₃) δ: 2.6-2.7 (m,2H), 2.9 (d, 2H), 3.4-3.5 (m, 1H), 3.72 (s, 3H), 3.82 (s, 3H), 6.6 (dd,1H), 6.73 (dd, 1H), 6.88 (t, 1H), 7.1-7.3 (m, 5H).

Step 6: 5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one

4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (37 g, 123 mmol), fromStep 5, was added dropwise to 200 g of polyphosphoric acid heated to100° C. The resultant mixture was stirred and heated at 100° C. for 0.25h. A mixture of 100 g of ice and 200 mL of water was added to thereaction mixture. The precipitate which formed was filtered, washed with3×75 mL of water and dissolved in 300 mL of methylene chloride. Themethylene chloride solution was dried over anhydrous magnesium sulfate,filtered and concentrated to give 28 g (81% yield) of5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, m.p;127°-128° C.; ¹ H NMR (CDCl₃) δ: 2.75-3.0 (m, 3H), 3.3-3.5 (m, 2H), 3.8(s, 3H), 3.95 (s, 3H), 693 (d, 1H), 7.25-7.4 (m, 5H), 7.9 (d, 1H).

Method B Step 1: 2-(2',3 '-Dimethoxyphenyl)-1,3-dithiane

A solution of 49.5 g (298 mmol) of 2,3-dimethoxybenzaldehyde and 48.4 g(447 mmol) of propane-1,3-dithiol in 800 mL of methylene chloride wascooled to 0° C. Boron trifluoride etherate (7.5 mL, 61 mmol) was addeddropwise to the cooled solution and the reaction mixture was stirred at0° C. for 0.5 h, then at ambient temperature for 18 h. The methylenechloride solution was washed with 2×200 mL of 10% aqueous sodiumhydroxide solution, 200 mL of water and 100 mL of brine, dried overanhydrous sodium sulfate and concentrated in vacuo to give 75 g (98%yield) of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane, m.p. 119°-120° C.; ¹ HNMR (CDCl₃) δ: 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.86 (t, 1H), 2.91 (t,1H), 3.05-3.2 (m, 2H), 3.83 (s, 3H), 3.91 (s, 3H), 5.68 (s, 1H), 6.86(dd, 1H), 7.07 (t, 1H), 7.19 (dd, 1H).

Step 2: Ethyl4-(2',3'-dimethoxyphenyl)-4-(1",3"-dithiane)-3-phenylbutyrate

A solution of 2-(2',3'-dimethoxyphenyl)-1,3-dithiane (57 g, 222 mmol),from Step 1, in 273 mL of dry THF was cooled to -78° C. in a dryice/acetone bath. To this solution was added 92.2 mL of a 2.5M solutionof n-butyl lithium in hexane. After the addition was complete thereaction mixture was stirred for 0.75 h at -78° C.1,3-Dimethyl-2-imidazolidinone (75 mL, 686 mmol), commercially availablefrom Aldrich Chemical Company, was added to the reaction mixture in oneportion, followed by 39 g (221 mmol) of ethyl cinnamate (commerciallyavailable from Aldrich Chemical Company) added dropwise. The reactionmixture was stirred for 1 h at -78° C. then quenched with 50 mL of 10%aqueous acetic acid and allowed to warm to 0° C. The reaction mixturewas diluted with 150 mL of diethyl ether and the layers separated. Theorganic layer was washed with 2×100 mL of saturated aqueous sodiumbicarbonate solution, 100 mL of water and 100 mL of brine, dried overanhydrous magnesium sulfate, filtered and concentrated to give a crudeoily product. The crude product was crystallized from ethylacetate/hexane to give 32 g (48% yield) of the title compound, m.p.125°-126° C. A second crop of crystals yielded an additional 11 g (totalyield 59%) of ethyl4-(2',3'-dimethoxyphenyl)-4-(1",3"-dithiane)-3-phenylbutyrate, m.p.124.5°-125° C.; ¹ H NMR (CDCl₃)δ: 0.8 (t, 3H), 1.75-1.9 (m, 2H),2.5-2.85 (m, 4H), 3.05-3.25 (m, 2H), 3.7-3.95 (m, 2H), 3.88 (s, 3H), 4.0(s, 3H), 4.45-4.5 (m, 1H), 6.8-6.9 (m, 2H), 7.0-7.4 (m, 6H).

Step 3: Ethyl 4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate

Ethyl 4-(2',3'-dimethoxyphenyl)-4-(1",3"-dithiane)-3-phenylbutyrate(14.5 g, 39 mmol), from Step 2, and 145 g Raney nickel and 300 mL ofabsolute ethanol were mixed together and heated at reflux temperatureunder 1 atmosphere of hydrogen for 3.25 h. The stirring was stopped andthe mixture was allowed to cool slightly before the solvent was decantedfrom the catalyst. An additional 300 mL of absolute ethanol was added tothe catalyst and the mixture stirred and heated to reflux. The stirringwas again stopped and the reaction mixture was allowed to cool slightlybefore the solvent was decanted from the catalyst. The combinedsupernatants were filtered through Celite® filter aid and concentratedin vacuo to give 10.8 g (97% yield) of ethyl4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate as a clear oil; ¹ H NMR(CDCl₃) δ: 1.11 (t, 3H), 3.07 (dd, 1H), 3.35 (dd, 1H), 3.81 (s, 3H),3.84 (s, 3H), 3.9-4.1 (m, 3H), 6.65 (dd, 1H), 6.77 (dd, 1H), 6.88 (t,1H), 7.2-7.4 (m, 5H).

Step 4: 4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric Acid

Ethyl 4-(2',3'-dimethoxyphenyl)-3-phenylbutyrate (40.3 g, 123 mmol),from Step 3, was dissolved in 400 mL of methanol and 62 mL of 3M aqueoussodium hydroxide solution was added in one portion. The reaction mixturewas stirred at ambient temperature for 18 h. The reaction mixture wasconcentrated and the residue was partitioned between 300 mL of diethylether and 200 mL of water. The layers were separated and the aqueouslayer was adjusted to pH 6 with 6M aqueous hydrochloric acid solutionand extracted with 3×200 mL of diethyl ether. The organic layers werecombined, washed with brine, dried over anhydrous magnesium sulfate,faltered and concentrated in vacuo to give 37 g (100% yield) of thetitle compound as a colorless oil. The ¹ H NMR spectrum was identical tothe spectrum reported for the product of Step 5 of Method A, Example 1.

Step 5: 5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one

4-(2',3'-Dimethoxyphenyl)-3-phenylbutyric acid (13.3 g, 44.3 mmol), fromStep 4, was treated with 14 mL (216 mmol) of methanesulfonic acid and200 mL of trifluoroacetic acid at 60° C. for 1.5 h. After cooling thereaction mixture, the trifluoroacetic acid was removed in vacuo and icewater was added to the residue. Methylene chloride was added and thelayers were separated. The organic layer was washed with 1N aqueoussodium hydroxide solution, water and brine, dried over anhydrousmagnesium sulfate, filtered and Concentrated under reduced pressure. Theresidue was recrystallized three times from methanol to give 9.6 g (77%yield) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one,m.p. 126°-128° C.; ¹ H NMR spectrum was identical to the spectrumreported for the product of Step 6 of Method A, Example 1.

EXAMPLE 2 1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthaleneStep 1:1-Aminomethyl-5,6-dimethoxy-1-hydroxy-3-phenyl-1,2,3,4-tetrahydronaphthalene

5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (14.6 g, 51.7mmol), from Example 1, 24 mL of acetonitrile, 10.3 g (104 mmol) oftrimethylsilylcyanide, commercially available from Aldrich ChemicalCompany, and 100 mg of aluminum chloride were mixed together and heatedat reflux temperature for 2.5 h. The reaction mixture was cooled andconcentrated. The residue was added dropwise to a solution of 4.3 g (113mmol) of lithium aluminum hydride in 101 mL of diethyl ether. After thereaction mixture was heated at reflux temperature for 2.5 h, 4.3 mL ofwater was added dropwise, followed by 4.3 mL of 15% aqueous sodiumhydroxide solution, followed by a second 4.3 mL of water. The reactionmixture was stirred until a granular precipitate formed. The solid wasfiltered and washed with 3×80 mL of methylene chloride. The filtrate wasconcentrated and the resultant solid was triturated with ethylacetate/hexane to give 11.9 g (73% yield) of the title compound, m.p.175°-176° C.; ¹ H NMR (d₆ -DMSO) δ: 2.03 (t, 1H), 2.28 (dt, 1H), 2.65(dd, 1H), 2.83 (dd, 1H), 2.95-3.1 (m, 2H), 3.28 (dd, 1H), 3.75 (s, 3H),3.86 (s, 3H), 6.87 (d, 1H), 7.2-7.4 (m, 6H).

Step 2: 1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthaleneHydrochloride

1-Aminomethyl-5,6-dimethoxy-1-hydroxy-3-phenyl-1,2,3,4-tetrahydronaphthalene(11.5 g, 37 mmol), from Step 1, was heated at reflux temperature in 300mL of isopropyl alcohol saturated with hydrochloric acid for 2 h. Theresultant solution was concentrated and the solid residue was trituratedwith hot toluene to give 10.6 g (98% yield) of1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalenehydrochloride, m.p. 189.5-190° C.; ¹ H NMR (d₆ -DMSO) δ: 2.78 (dd, 1H),3.11 (dd, 1H), 3.2-3.4 (m, 2H+H₂ O), 3.6 (s, 3H), 3.81 (s, 3H), 3.93 (d,1H), 6.1 (d, 1H), 6.93 (d, 1H), 7.12 (d, 1H), 7.2-7.4 (m, 5H).

Step 3; 1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthaleneHydrobromide (Example 2A)

1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalenehydrochloride (6.0 g, 20.2 mmol), from Step 2, was suspended in 200 mLof methylene chloride and boron tribromide (90.5 mL of 1M solution ofBBr₃ in methylene chloride) was added dropwise while the reactionmixture was being cooled (to -78° C.) in a dry ice/acetone bath. Thereaction mixture was warmed to 0° C. and stirred for 0.5 h, then againcooled to -78° C. in a dry ice/acetone bath. Methanol (50 mL) was addeddropwise to the reaction mixture, which was allowed to warm to ambienttemperature then concentrated in vacuo. Methanol was added to theresidue and the solution was reconcentrated. This residue was dissolvedin a small amount of methanol and the methanol solution was added to 700mL of diethyl ether. The precipitate which formed was filtered, washedwith diethyl ether and recrystallized from methanol/ether to give 2.5 g(45% yield) of the title compound, m.p. 223°-225° C. ¹ H NMR (d₆ -DMSO)δ: 2.68 (dd, 1H), 3.09 (dd, 1H), 3.6-3.7 (m, 1H), 3.9 (s, 2H), 5.97 (d,1H), 6.69 (m, 2H), 7.2-7.35 (m, 5H), 8.1 (br s, 3H), 8.4 (s, 1H), 9.5(s, 1H).

Step 4: 1-Aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthaleneHydrochloride (Example 2B)

A slurry of 10 g (25 mmol) of1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalenehydrochloride, from Step 2, in 150 mL of 1,2-dichloroethane was cooledto 10° C. under a nitrogen atmosphere. Boron trichloride was passedthrough the reaction mixture until 27 g (230 mmol) had been added. Thereaction mixture was allowed to warm to ambient temperature and stirredfor 18 h. The reaction mixture was then cooled in ice and 100 mL ofmethanol was added dropwise. The reaction mixture was again allowed towarm to ambient temperature and concentrated in vacuo. Twice, 500 mLportions of methanol were added to the residue and it wasreconcentrated. The resultant foam was dissolved in 40 mL of ethanol,filtered and the solution was treated with 40 mL of methylene chlorideand 80 mL of heptane. Off- white crystals of1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalenehydrochloride (5.1 g, 56% yield) were collected by filtration, m.p.204°-205° C. The ¹ H NMR spectrum was identical to the spectrum for theproduct of Example 2A.

EXAMPLE 3 5,6-Bis(acetoxy)-1-aminomethyl-3-phenyl-3,4-dihydronaphthaleneHydrochloride

A suspension of 7.6 g (25 mmol) of1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalenehydrochloride (Example 2B) in 400 mL of acetic anhydride saturated withanhydrous hydrogen chloride was stirred at ambient temperature for 48 h.Approximately 2L of diethyl ether was added and a solid was collected byfiltration and washed with diethyl ether. Crystallization of the crudematerial (6.7 g) was achieved by dissolving the powder in 400 mL of hotethanol, adding 100 mL of water, filtering the solution hot and allowingit to cool. The white crystals which formed were filtered and dried togive 2.8 g (29% yield) of5,6-bis(acetoxy)-1-aminomethyl-3-phenyl-3,4-dihydronaphthalenehydrochloride, m.p. 207°-208° C. ¹ H NMR (d₆ -DMSO) δ: 2.28 (s, 6H),2.62 (dd, 1H), 2.95 (dd, 1H), 3.7-3.8 (m, 1H), 3.97 (s, 2H), 6.25 (d,1H), 7.19 (d, 1H), 7.2-7.4 (m, 6H), 8.41 (br s, 3H).

EXAMPLE 45,6-Bis(acetoxy)-1-(alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthaleneHydrochloride (General Procedure for Preparation of Amino Prodrugs) Step1:5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl-alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene

N-t-Butoxycarbonyl-alanyl-alanine (BocAla-Ala) (2.01 g, 7.74 mmol) wasadded to a stirred solution of1-aminomethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthalenehydrochloride (3 g, 7.74 mmol), the product of Example 3, in 35 mL ofDMF. The resultant solution was cooled to 0° C. To the cold solution wasadded 1.56 g (8.13 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),followed approximately 10 minutes later by 1.1 g (8.13 mmol) of1-hydroxybenzotriazole hydrate (HOBT) and, after allowing the HOBT todissolve, by 1.8 g (16 mmol) of 4-methylmorpholine (NMM). The resultantsolution was stirred for 3 h at 0° C. and then stirred overnight atambient temperature. The reaction mixture was then diluted with 100 mLof water and the resultant milky mixture was extracted with 3×75 mL ofethyl acetate. The combined organic layers were washed successively with50 mL of 1M aqueous phosphoric acid solution, 50 mL of saturated aqueoussodium bicarbonate solution, 2×50 mL of water and 50 mL of brine. Theorganic layer was then dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo to a light yellow colored foam. The foam (5.06g) was purified by flash chromatography using C₁₈ ODS (C₁₈-octadecylsilane) on silica as the solid phase and a 50% solution of 1%aqueous trifluoroacetic acid (TFA) in acetonitrile as the eluent to give2.03 g (44% yield) of the title compound as a light yellow coloredsolid, m.p. 114°-116° C.; ¹ H NMR (CDCl₃) δ: 1.23 (q, 3H), 1.35 (q, 3H),1.42 (s, 9H), 2.23 (s, 3H), 2.28 (s, 3H), 2.70 (m, 1H), 2.95 (dd, 1H),3.68 (m, 1H), 4.05 (q, 1H), 4.2-4.47 (m, 3H), 6.01 (d, 1H), 7.04 (d,1H), 7.17 (d, 1H), 7.26 (m, 5H).

Step 2: 5,6-Bis(acetoxy)-1-(alanyl,alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene Hydrochloride

5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl-alanyl-alanyl)aminomethyl-3-phenyl-3,4-dihydronaphthalenehydrochloride (2.00 g, 3.36 mmol) from Step 1 was dissolved in 25 mL ofdiethyl ether. The resultant solution was cooled and saturated withhydrogen chloride. The solution was stirred at ambient temperature for 3h. The precipitate was filtered and washed thoroughly with dry diethylether. The solid was dried overnight at 60° C. in vacuo to give 1.69 g(95% yield) of the title compound as an off-white solid, m.p. 145°-161°C. (dec); ¹ H NMR (CDCl₃) δ: 1.35 (dd, 3H), 1.41 (m, 3H), 2.23 (s, 3H),2.26 (s, 3H), 2.70 (dt, 1H), 2.95 (dd, 1H), 3.69 (br s, 1H), 3.89 (dq,1H), 4.17-4.45 (m, 3H), 6.11 (d, 1H), 7.07 (d, 1H), 7.25 (m, 6H), 8.27(m, 1H). Analysis calculated for C₂₇ H₃₃ N₃ O₆ +1.3HCl: C, 59.73; H,6.37; N, 7.74. Found: C, 59.94; H, 6.08; N, 7.64.

EXAMPLE 51-Aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthaleneHydrochloride Step 1:N-t-Butyloxycarbonyl-1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene

Triethylamine (7 mL) was added to a solution of 15 g (56 mmol) of1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalenehydrochloride, from Example 2 in 100 mL of dimethylformamide (DMF). Thesolution was cooled to 0° C. and a solution of di-t-butyldicarbonate (18g, 82.5 mmol) in 50 mL of DMF was added over a period of 1 h. After theaddition was complete, 250 mL of water was added to the reaction mixtureand it was extracted with ethyl acetate. The combined organic layersfrom the extraction were washed with 1N hydrochloric acid solution andbrine, dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo. The brown residue was triturated with boiling hexanes to give16.7 g (99% yield) of the title compound as an off-white solid, m.p.175°-177° C., ¹ H NMR δ: 1.45 (s, 9H), 2.74 (dd, 1H), 3.19 (dd, 1H),3.6-3.7 (m, 1H), 4.1-4.25 (m, 2H), 4.71 (br s, 1H), 5.4 (br s, 1H), 5.88(d, 1H), 6.0 (br s, 1H), 6.68 (s, 2H), 7.2-7.35 (m, 5H).

Step 2:N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene

N-t-Butyloxycarbonyl-1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalene(3 g, 8.16 mmol), from Step 1, and 11 mL of triethylamine were combinedand cooled to 0° C. A solution of trimethylacetyl chloride (2.1 mL, 17mmol) in 13 mL of dioxane was added to the cooled solution dropwise. Thereaction mixture was allowed to warm to ambient temperature and stirredat ambient temperature for 2 h. Water (25 mL) was added to the reactionmixture and the pH was adjusted to 4 with concentrated phosphoric acid.The reaction mixture was extracted with diethyl ether. The combinedether extracts were washed with aqueous saturated sodium bicarbonatesolution, water and brine, dried over anhydrous magnesium sulfate,faltered and concentrated in vacuo to give 4.26 g (89% yield) ofN-t-butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthaleneas an off-white solid, m.p. 64°-69° C.; ¹ H NMR (CDCl₃) δ: 1.3 (s, 9H),1.34 (s, 9H), 1.45 (s, 9H), 2.68 (dd, 1H), 2.93 (dd, 1H), 3.6-3.75 (m,1H), 4.1-4.3 (m, 2H), 4.63 (br s, 1H), 6.03 (d, 1H), 6.98 (d, 1H),7.15-7.35 (m, 6H).

Step 3:1-Aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthaleneHydrochloride

N-t-Butyloxycarbonyl-1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalene(14 g, 26 mmol), from Step 2, was dissolved in 75 mL of dioxane andsaturated with anhydrous hydrogen chloride. The reaction mixture wasstirred for 2 h and concentrated in vacuo. The solid residue wasdissolved in a minimum amount of methanol and the methanol solution wasadded dropwise to an excess amount (500 mL) of diethyl ether. Theprecipitate was filtered, washed with diethyl ether and dried to give9.1 g (90% yield) of1-aminomethyl-5,6-bis(trimethylacetoxy)-3-phenyl-3,4-dihydronaphthalenehydrochloride as a white powder, m.p. 210°-212° C.; ¹ H NMR (d₆ -DMSO)δ: 1.25 (s, 9H), 1.28 (s, 9H), 2.61 (dd, 1H), 2.89 (dd, 1H), 3.75-3.85(m, 1H), 3.99 (s, 2H), 6.28 (d, 2H), 7.15 (d, 1H), 7.2-7.35 (m, 5H),7.37 (d, 1H), 8.37 (br s, 3H).

EXAMPLES 6-15

Following the procedures described in Example 4 using the appropriateaminomethyl compound of formula I with both catechol hydroxyl groupprotected as shown in the table and the appropriate (D) or (L) aminoacid or peptide having the N-terminal amino group protected preferablyas a carbamate, and more preferably as the- t-butoxycarbonyl derivative,Examples 5-14 were prepared as disclosed below in Table 1.

EXAMPLES 16-34

Following the procedures described in Example 15, replacing thetrimethylacetyl chloride with R1-Cl, where R1 is as shown in the table,Examples 16-34 were prepared as disclosed below in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Examples 6-15                                                                  ##STR11##                                                                                              MS.sup.a                                            Ex. #                                                                             R1      R5       mp °C.                                                                      (M + H).sup.+                                                                              C   H  N                               __________________________________________________________________________    6   acetyl  CO.sub.2 CH(CH.sub.3)                                                                  oil  499    calc: 64.85                                                                             5.65                                                                             2.91                                        OCOCH.sub.3   (M + NH.sub.4).sup.+                                                                 found:                                                                              64.68                                                                             5.99                                                                             2.74                            7   acetyl  γ-L-glutamyl                                                                     142-177                                                                            481    calc: 481.1975.sup.b                                              (dec)       found:                                                                              481.1696                               8   acetyl  L-leucyl 187-192                                                                            451    calc: 62.01                                                                             6.30                                                                             5.48                                                 (dec)       found:                                                                              62.39                                                                             6.54                                                                             5.60                            9   acetyl  α-L-aspartyl                                                                     150(dec)                                                                           467    calc: 57.32                                                                             5.33                                                                             5.33                                                             found:                                                                              57.44                                                                             5.63                                                                             5.36                            10  acetyl  L-alanyl 150-158                                                                            423    calc: 61.28                                                                             5.93                                                                             6.15                                                 (dec)       found:                                                                              61.60                                                                             6.03                                                                             5.99                            11  acetyl  D-alanyl 150-157                                                                            423    calc: 61.06                                                                             5.89                                                                             6.09                                                 (dec)       found:                                                                              61.13                                                                             6.07                                                                             5.94                            12  acetyl  L-norvalyl                                                                             136(dec)                                                                           451    calc: 62.95                                                                             6.47                                                                             5.79                                                             found:                                                                              62.96                                                                             6.50                                                                             5.65                            13  acetyl  L-prolyl 150-152                                                                            449    calc: 60.31                                                                             5.82                                                                             5.41                                                 (dec)       found:                                                                              60.19                                                                             5.79                                                                             5.51                            14  acetyl  L-methionyl                                                                            135-142                                                                            483    calc: 59.19                                                                             6.00                                                                             5.40                                                 (dec)       found:                                                                              59.14                                                                             6.11                                                                             5.30                            15  benzoyl L-alanyl-                                                                              184-185                                                                            618    calc: 63.55                                                                             5.00                                                                             5.76                                        L-alanyl (dec)       found:                                                                              63.54                                                                             4.96                                                                             5.72                            16  benzoyl H        173-182     calc: *see example 16 detail                                                  found:                                                                              following table                        17  butanoyl                                                                              H        145-150                                                                            408    calc: 66.29                                                                             6.90                                                                             3.09                                                 (dec)       +0.5                                                                          H.sub.2 O                                                                     found:                                                                              65.98                                                                             6.80                                                                             2.96                            18  iso-    H        na   408    calc: 67.09                                                                             6.85                                                                             3.13                                butanoyl                     +0.2                                                                          H.sub.2 O                                                                           6                                                                       found:                                                                              7.04                                                                              6.79                                                                             3.11                            19  methyl  H        116-188                                                                            496    calc: 60.96                                                                             5.68                                                                             2.63                                succinoyl                    found:                                                                              60.87                                                                             5.66                                                                             2.72                            20  propionyl                                                                             H        111-112                                                                            380    calc: +                                                                             62.20                                                                             6.74                                                                             2.57                                                             1.75H.sub.2 O                                                                 found:                                                                              62.20                                                                             6.74                                                                             2.26                            21  CONH    H        na   na     calc:                                            phenyl                       found:                                                                              na                                     22  acetyl.sup.c                                                                          H        252  354    calc: 64.69                                                                             6.20                                                                             3.59                                                             +0.5                                                                          H.sub.2 O                                                                           63.36                                                                             6.10                                                                             3.48                                                             found:                                       23  methoxy-                                                                              H        135-138                                                                            384    calc: 58.81                                                                             5.40                                                                             3.27                                carbonyl                     +0.5                                                                          H.sub.2 O                                                                           58.64                                                                             5.25                                                                             3.25                                                             found:                                       24  isobutyl                                                                              H        112-114                                                                            552    calc: 63.12                                                                             6.53                                                                             2.37                                succinoyl                    +0.1                                                                          H.sub.2 O                                                                           62.74                                                                             6.50                                                                             2.30                                                             found:                                       25  dimethyl-                                                                             H        100-103                                                                            410    calc: +1.1                                                                          61.95                                                                             6.33                                                                             9.42                                amino-                       H.sub.2 O                                        carbonyl                     +0.3                                                                          EtOAc 58.83                                                                             6.29                                                                             8.19                                                             found:                                       26  trifluoromethyl-                                                                      H        128-130                                                                            532    calc: +0.1                                                                          40.18                                                                             2.84                                                                             2.47                                sulfonyl                     C.sub.6 H.sub.14                                                              found:                                                                              41.07                                                                             2.93                                                                             2.50                            27  beta-alanyl                                                                           H        219  na     calc:                                                                         found:                                                                              na                                     28  (1,2-   H        245(dec)                                                                           294    calc: 65.56                                                                             4.89                                                                             4.25                                carbonyl)                    +0.1                                                                          H.sub.2 O                                                                           65.08                                                                             4.91                                                                             4.17                                                             found:                                       29  ethoxycarbonyl                                                                        H        130-132                                                                            412    calc: 61.06                                                                             5.90                                                                             3.10                                                             found:                                                                              61.21                                                                             5.97                                                                             3.05                            30  CONH    H        214-215                                                                            534    calc: 69.53                                                                             5.66                                                                             7.37                                benzyl                       +0.5                                                                          H.sub.2 O                                                                           68.11                                                                             5.57                                                                             7.18                                                             found:                                       31  CONH    H        205-206                                                                            382    calc: 60.36                                                                             5.79                                                                             10.06                               methyl                       found:                                                                              59.08                                                                             5.93                                                                             9.23                            32  acetyl  COO      161-162                                                                            469    calc: 69.16                                                                             6.47                                                                             3.10                                t-butyl               found: 68.93 6.45                                                                              3.10                               33  p-      H        150(dec)                                                                           566    calc: 61.84                                                                             4.01                                                                             6.98                                nitrobenzoyl                 found:                                                                              61.55                                                                             4.04                                                                             6.86                            34  p-methoxy-                                                                            H        159-161                                                                            536    calc: 67.17                                                                             5.47                                                                             2.37                                benzoyl                      }30 1 H.sub.2 O                                                               found:                                                                              67.16                                                                             5.24                                                                             2.35                            __________________________________________________________________________     .sup.a Mass spectral M/Z (DCI/NH.sub.3)                                       .sup.b High Resolution mass spectral analysis                                 .sup.c starting from compound of Example 35 instead of Example 5.             .sup.d structure confirmed by NMR data                                   

EXAMPLE 161-Aminomethyl-5,6-bis(benzoyloxy)-3-phenyl-3,4-dihydronaphthaleneHydrochloride

Following the procedures described in Example 5, replacingtrimethylacetyl chloride with benzoyl chloride and1-aminomethyl-5,6-dihydroxy-3-phenyl-3,4-dihydronaphthalenehydrochloride with the compound of Example 15, the title compound wasprepared. m.p. 173°-182° C.; ¹ H NMR (CD₃ OD) δ: 2.88 (t, 1H), 3.05 (dd,1H), 3.65-3.8 (m, 2H), 4.0-4.1 (br s, 1H+CH3OH), 6.35 (d, 1H), 7.05-7.35(m, 10H), 7.35-7.55 (m, 3H), 7.9-8.0 (m, 4H), 8.5-8.65 (br s, 3H).

EXAMPLE 35[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydronaphthaleneHydrobromide Step 1:[1,3-cis]1-Aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthaleneHydrochloride

To 0.2 g (0.67 mmol) of1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalenehydrochloride, from Step 2, of Example 2, was added 0.05 g of 10%palladium supported on carbon. The reaction mixture was sealed underhydrogen and stirred overnight at ambient temperature. The reactionmixture was flushed with nitrogen before it was filtered through Celite®filter aid and washed with 15 mL of absolute ethanol and 15 mL ofmethylene chloride. The filtrate was concentrated to give 0.2 g (100%yield) of[1,3-cis]1-aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalenehydrochloride, m.p. 230-231° C.; ¹ H NMR (d₆ -DMSO) δ: 2.15-2.25 (m,1H), 2.5-2.65 (m, 1H), 2.8-2.95 (m, 2H), 3.0-3.1 (m, 1H), 3.1-3.4 (m,1H), 3.45-3.5 (m, 1H), 3.66 (s, 3H), 3.78 (s, 3H), 6.95 (d, 1H), 7.12(d, 1H), 7.2-7.3 (m, 1H), 7.35-7.45 (m, 4H), 8.0 (br s, 3H).

Step 2:[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydronaphthaleneHydrobromide

[1,3-cis]1-Aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalenehydrochloride (0.2 g, 0.67 mmol), from Step 1, was suspended in 13 mL ofmethylene chloride and the suspension was cooled to -78° C. in a dryice/acetone bath. Boron tribromide (3 mL of a 1M solution in methylenechloride, 3 mmol) was added and the reaction mixture was allowed to warmto ambient temperature, kept at ambient temperature for 1.5 h thencooled to -78° C. Methanol (3 mL) was added to the reaction mixture andit was again allowed to warm to ambient temperature then concentrated invacuo. The residue was redissolved in methanol and reconcentrated. Theresidue was again redissolved in methanol and the methanol solution wasadded to a large excess of diethyl ether. The resultant precipitate wasfiltered and recrystallized from ethanol/diethyl ether to give 0.14 g(64% yield) of the title compound as a whim powder, m.p. 256°-259° C.; ¹H NMR (d₆ -DMSO) δ: 1.63 (q, 1H), 2.1-2.25 (m, 1H), 2.4-2.5 (m, 1H),2.75-2.95 (m, 2H), 3.02 (dd, 1H), 3.15-3.3 (m, 1H), 3.4-3.5 (m, 1H),6.68 (s, 2H), 7.2-7.3 (m, 1H), 7.3-7.4 (m, 4H), 7.8 (br s, 3H), 8.2 (brs, 1H), 9.1 (br s, 1H).

EXAMPLE 361-Aminomethyl-3-cyclohexyl-5,6-dihydroxy-3,4-dihydronaphthaleneHydrobromide Step 1: Ethyl 3-cyclohexylpropenoate

Sodium hydride (2.6 g, 108 mmol) was added to 100 mL of THF and 19.8 mL(98.9 mmol) of triethylphosphonoacetate, commercially available fromAldrich Chemical Company, was added dropwise at 0° C. The reactionmixture was stirred for 1 h at ambient temperature and 12.1 mL (99.9mmol) of cyclohexanecarboxaldehyde, commercially available from AldrichChemical Company, was added. The reaction mixture was heated at refluxtemperature for 15 min then cooled and filtered. The filtrate wasconcentrated under reduced pressure and the product was distilled at140° C. (15 Torr) to give 15.2 g (84% yield) of ethyl3-cyclohexylpropenoate as a clear liquid; ¹ H NMR (CDCl₃) δ: 1.1-1.4 (m,6H), 1.3 (t, 3H), 1.6-1.8 (m, 5H), 2.05-2.2 (m, 1H), 4.2 (q, 2H), 5.75(d, 1H), 6.92 (d, 1H).

Step 2: 1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthaleneHydrochloride

2-(2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, MethodB, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, werecondensed as described in Step 2 of Example 1, Method B. The adduct wastreated with Raney nickel and sodium hydroxide to give the correspondingacid. The acid was cyclized with polyphosphoric acid as described inStep 6 of Example 1, Method A, to give3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one. Thisketone was treated with trimethylsilylcyanide in the presence ofaluminum chloride and reduced with lithium aluminum hydride as describedin Step 1 of Example 2 to give1-aminomethyl-5,6-dimethoxy-1-hydroxy-3-cyclohexyl-1,2,3,4-tetrahydronaphthalene.The hydroxy group was eliminated by treatment with anhydrous hydrogenchloride in isopropyl alcohol as described in Step 2 of Example 2 togive 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalenehydrochloride, m.p. 178°-179° C.; ¹ H NMR (d₆ -DMSO) δ: 1.0-1.4 (m, 7H),1.5-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 (s,3H), 3.81 (s, 3H), 5.8 (d, 1H), 6.6 (m, 2H).

Step 3: 1-Aminomethyl-3-cyclohexyl-5,6-dihydroxy-3,4-dihydronaphthaleneHydrobromide

1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalenehydrochloride (2.7 g, 8.9 mmol), from Step 2, was dissolved in 72 mL ofmethylene chloride and cooled to -78° C. Boron tribromide (36 mL of a 1Msolution in methylene chloride) was added and the reaction mixture waswarmed to 0° C. for 1 h. The reaction mixture was cooled again to -78°C. and 30 mL of methanol was added. After stirring at ambienttemperature for 1 h, the reaction mixture was concentrated, diluted withmethanol and reconcentrated. The residue was dissolved in methanol andthe methanol solution was added dropwise to an excess amount of diethylether. The precipitate was filtered and recrystallized fromethanol/ether to give 2.2 g (79% yield) of the title compound, m.p.212°-213° C.; ¹ H NMR (d₆ -DMSO) δ: 1.0-1.4 (m, 7H), 1.55-1.9 (m, 6H),2.05-2.15 (m, 1H), 2.47 (dd, 1H), 2.74 (dd, 1H), 5.83 (d, 1H), 6.60 (m,2H).

EXAMPLE 37[1R,3S]1-Aminomethyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthaleneHydrobromide Step 1:[1R,3S]1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthaleneHydrochloride

1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalenehydrochloride (1 g, 3.3 mmol), from Step 2 of Example 36, was dissolvedin 20 mL of ethanol and 0.25 g of 10% palladium on carbon was added tothe ethanol solution. The reaction mixture was sealed under oneatmosphere of hydrogen and shaken at ambient temperature for 24 h. Thereaction mixture was filtered to remove the catalyst and concentrated togive 1 g (100% yield) of the title compound, m.p. 282°-283° C.; ¹ H NMR(d₆ -DMSO) δ: 1.0-1.5 (m, 8H), 1.5-1.9 (m, 5H), 2.0-2.2 (m, 2H), 2.7-3.1(m, 3H), 3.3-3.4 (m, 1H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4-6.8 (m, 2H).

Step 2:[1R,3S]1-Aminomethyl-3-cyclohexyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthaleneHydrobromide

[1R,3S]1-Aminomethyl-3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalenehydrochloride (0.7 g, 2.3 mmol), from Step 1, was suspended in 20 mL ofmethylene chloride at -78° C. Boron tribromide (9.7 mL of a 1M solutionin methylene chloride, 9.7 mmol) was added and the reaction mixture wasallowed to warm to ambient temperature. After stirring at ambienttemperature for 1 h, the reaction mixture was cooled to -78° C. and 10mL of methanol was added. The reaction mixture was again allowed to warmto ambient temperature and stirred at ambient temperature for 1 h. Thesolvent was removed in vacuo and methanol was added to the residue. Themethanol solution was concentrated and the residue dissolved in aminimal amount of methanol and added dropwise to a large excess ofdiethyl ether. The precipitate was filtered and recrystallized fromethanol/diethyl ether to give 0.48 g (65% yield) of [1R,3S]1-aminomethyl-3-cyclohexyl-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalenehydrobromide, m.p. 203°-204° C.; ¹ H NMR (d₆ -DMSO) δ: 0.9-1.5. (m, 8H),1.6-1.9 (m, 5H), 2.0-2.1 (m, 2H), 2.7-3.0 (m, 3H), 3.3-3.4 (m, 1H),6.5-6.7 (m, 2H).

EXAMPLES 38-43

Following the synthesis outlined in Example 36, using the appropriatealdehyde, Examples 38-43 were made, as their hydrochloride salts, asdisclosed in Table 2. The structure of each was confirmed by meltingpoint (m.p.), elemental analysis and mass spectra as designated.Examples 42 and 43, as disclosed in Table 2, were prepared, using theappropriate aldehyde, following sequentially the procedures described inExamples 37 and 38, as their hydrochloride salts. The structure of eachwas confirmed by melting point (m.p.), elemental analysis and massspectra as designated.

                                      TABLE 2                                     __________________________________________________________________________    Examples 38-43                                                                Ex-                                                                           am-                                                                           ple                                     m.p.    Elemental Analysis            #  Compound*             Aldehyde       °C.                                                                        MS**     C   H  N                 __________________________________________________________________________    38                                                                               ##STR12##                                                                                            ##STR13##     210 284 calc: + 3/4 H.sub.2 O                                                         Found:                                                                             54.05 53.95                                                                       5.20 4.97                                                                        3.71 3.86         39                                                                               ##STR14##                                                                                            ##STR15##     223-6                                                                             284 calc: +0.1 H.sub.2 O                                                          Found:                                                                             55.78 55.64                                                                       5.01 5.25                                                                        3.38 3.74         40                                                                               ##STR16##                                                                                            ##STR17##     >225    calc: Found:                                                                       na***                    41                                                                               ##STR18##                                                                                            ##STR19##     192-8                                                                             318 calc: Found:                                                                       na***                    42                                                                               ##STR20##                                                                                            ##STR21##     250° C.                                                                    286 calc: +1 H.sub.2 O                                                                 53.13 52.97                                                                       5.77 5.53                                                                        3.65 4.03         43                                                                               ##STR22##                                                                                            ##STR23##     190-6                                                                             320 calc: Found:                                                                       na***                    __________________________________________________________________________     *all compounds 1-3 cis unless indicated otherwise                             **DCl MS (M + H).sup.+ -                                                      ***structure confirmed by NMR data                                       

EXAMPLE 441-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3,4-dihydronaphthaleneHydrobromide Step 1:2-(Carboethoxy)methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaph-thalen-1-one

To a solution of5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (5 g, 17.7mmol, 1.0 equivalents), the product of Example 1, in 150 mL of dry THFcooled to -78° C., was added 19.5 mL of lithium bis(trimethylsilyl)amide(1M solution in THF, 19.5 mmol, 1.1 equivalent). The resultant solutionwas stirred at -78° C. for 1 h and then ethyl bromoacetate (2.2 mL, 19.5mmol, 1.1 equivalent) was added in one portion. The reaction solutionwas then allowed to warm to ambient temperature and was stirred for 3 h.The reaction was quenched by the addition of 50 mL of saturated ammoniumchloride solution. The resultant light yellow colored THF layer wasseparated and evaporated to an oil. The oil was taken up into 200 mL ofmethylene chloride and the methylene chloride solution was washed with2×50 mL of water and 50 mL of brine, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue waschromatographed on silica gel eluted with ethyl acetate/hexane (1:6) togive 5.4 g (83% yield) of the title compound as a white solid; ¹ H NMR(CDCl₃) δ: 1.2 (t, 3H, J=7.5 Hz), 2.45 (m, 2H), 3.03 (m, 1H), 3.30 (m,2H), 3.43 (m, 1H), 3.78 (s, 3H), 3.93 (s, 3H), 4.07 (m, 2H), 6.92 (d,1H, J=9.0 Hz), 7.32 (m, 5H), 7.89 (d, 1H, J=9.0 Hz). Analysis calculatedfor C₂₂ H₂₄ O₅ : C, 71.72; H, 6.57. Found: C, 71.39; H, 6.63.

Step 2:9b-Cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9b-hexahydronaphtho[1,2b]furan

To a solution of2-(carboethoxy)methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one(1.0 g, 2.7 mmol, 1.0 equivalent) from Step 1, in 10 mL of anhydroustoluene at ambient temperature was added 5.4 mL of diethylaluminumcyanide (1M solution in toluene, 5.4 mmol, 2.0 equivalents). Theresultant solution was stirred at ambient temperature for 1 h and thenpoured with vigorous stirring into a mixture of 15 mL of concentratedhydrochloric acid and 70 mL of ice water. The organic layer was dilutedwith 75 mL of methylene chloride and then separated from the aqueouslayer. The organic layer was washed with 25 mL of 2M anhydroushydrochloric acid solution, 25 mL of water and 25 mL of brine, driedover anhydrous magnesium sulfate, filtered and concentrated to give 1 g(105% crude yield) of the title compound as an oily residue. The crudeproduct was carried on to the next step without purification; ¹ H NMR(CDCl₃) δ: 2.45 (d, 1H, J=18.0 Hz), 2.72 (m, 2H), 3.05 (m, 1H), 3.23 (m,1H), 3.37 (m, 1H), 3.79 (s, 3H), 3.94 (s, 3H), 7.0 (d, 1H), 7.30 (m,5H), 7.52 (d, 1H, J=9.0 Hz).

Step 3:1-Aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3,4-dihydronaphthaleneHydrochloride

To a stirred solution of9b-cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9b-hexahydronaphtho[1,2b]furan(1.0 g, 2.86 mmol, 1.0 equivalent), from Step 2, in 30 mL of anhydrousTHF, was added lithium aluminum hydride (0.22 g, 5.7 mmol, 2.0equivalents) from a solid addition funnel. After the addition wascomplete, the reaction mixture was heated at reflux for 3 h. Thereaction mixture was then cooled, poured into a 250 mL Erlenmeyer flaskand was diluted with 50 mL of anhydrous THF. The reaction was quenchedby the addition of excess sodium sulfate decahydrate. The resultantsuspension was filtered through Celite® filter lo aid and the filtercake was washed with 100 mL of hot THF. The filtrate was concentrated toa light amber colored foam. This foam was dissolved in a solution of 3Manhydrous hydrochloric acid in isopropanol and the resultant solutionwas heated at reflux for 18 h. The solution was then concentrated invacuo. The residue was triturated with methylene chloride/diethyl ether(1:1) to give 250 mg (25% yield) of the title compound; ¹ H NMR (CDCl₃)δ: 2.03 (m, 1H), 2.63 (m, 1H), 3.12 (m, 2H), 3.37 (s, 3H), 3.52 (m, 3H),3.52 (m, 3H), 3.71 (s, 3H), 3.80 (m, 1H), 4.18 (m, 2H), 5.28 (br s, 1H),6.23 (d, 1H, J=8 Hz), 6.95-7.4 (m, 6H). Analysis calculated for C₂₁ H₂₆ClNO₃ +1.5 H₂ O: C, 54.16; H, 6.40; N, 2.87. Found: C, 54.15; H, 6.01;N, 3.01.

Step 4:1-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3,4-dihydronaphthaleneHydrobromide

To a solution of1-aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-3,4-dihydronaphthalenehydrochloride (60 mg, 0.177 mmol, 1.0 equivalent), from Step 3, in 2 mLof anhydrous methylene chloride cooled to -78° C. was added 350 μL ofboron tribromide (1.0M solution in methylene chloride, 0.35 mmol, 2.0equivalents). The resultant solution was allowed to warm to ambienttemperature gradually over a period of 2 h and then it was again cooledto -78° C. and quenched by the addition of 20 mL of anhydrous methanol.The solid was filtered and recrystallized from a mixture of methanol,methylene chloride and diethyl ether to give 50 mg (80% yield) of thetitle compound as a white powder, m.p. 252°-255° C.; DCI MS M/Z: 312(M+H)⁺ ; I.R. (KBr): 3400, 1600, 1490, 1280, 1200, 700 cm⁻¹ ; ¹ H NMR(CD₃ OD) δ: 2.22 (m, 1H), 2.75 (m, 1H), 2.93 (m, 1H), 3.30 (m, 1H), 3.70(m, 3H), 4.13 (d, 1H, J=12 Hz), 4.28 (d, 1H, J=13.5 Hz), 6.70 (d, 1H,J=7.5 Hz), 6.85 (d, 1H, J=7.5 Hz), 7.10 (m, 5H). Analysis calculated forC₉ H₂₂ BrNO₃ +0.5 CH₂ Cl₂ : C, 53.87; H, 5.33; N, 3.22. Found: C, 53.54;H, 5.24; N, 3.21.

EXAMPLE 45[1,2-trans]1-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-1,2,3,4-tetrahydronaphthaleneFormic Acid Salt Step 1:[1-2-trans]2-(Carboethoxy)methyl-1-cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene

9b-Cyano-6,7-dimethoxy-2-oxo-4-phenyl-2,3,3a,4,5,9b-hexahydro-naphtho[1,2b]furan(5.0 g, 14.31 mmol, 1.0 equivalents), the product of Step 2 of Example44, was dissolved in 120 mL of a solution of 2M anhydrous hydrochloricacid in ethanol and the resultant solution was heated at reflux for 2 h.The solvent was evaporated in vacuo and the residue was dissolved in 120mL of methylene chloride. The methylene chloride solution was washedwith 2×25 mL of saturated aqueous sodium bicarbonate solution, 25 mL ofwater and 25 mL of brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give 5 g (93% yield) of the titlecompound as a colorless oil; ¹ H NMR (CDCl₃) δ: 1.22 (t, 3H, J=7.5 Hz),3.24 (m, 3H), 3.54 (s, 3H), 3.70 (d, 1H, J=15 Hz), 3.58 (s, 3H), 3.90(m, 1H), 4.08 (m, 2H), 6.82 (d, 1H, J=7.0 Hz), 7.03 (m, 2H), 7.20 (m,3H), 7.30 (d, 1H, J=7.0 Hz).

Step 2:[1-2-trans]1-Aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-1,2,3,4-tetrahydronaphthalene

To a stirred solution of2-(carboethoxy)methyl-1-cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene(2 g, 5.3 mmol, 1.0 equivalent), from Step 1, in 50 mL of anhydrousmethanol at ambient temperature, was added 5.13 g (212 mmol, 40equivalents) of magnesium powder. The resultant mixture was stirred atambient temperature for 2 h and then it was cooled to 0° C. The reactionwas quenched by the slow addition of 150 mL of 2N aqueous hydrochloricacid solution. The aqueous solution was extracted with 4×50 mL ofmethylene chloride. The combined organic layers were washed with 50 mLof water and 50 mL of brine, dried over anhydrous magnesium sulfate,filtered and concentrated to a colorless oil. The oil was dissolved in75 mL of anhydrous THF. To this solution at 0° C. was added 0.4 g (10.5mmol, 2.0 equivalents) of lithium aluminum hydride. The resultantmixture was heated at reflux for 4 h and then diluted with 100 mL ofanhydrous THF. The reaction was quenched by the addition of sodiumsulfate decahydrate. The reaction mixture was then faltered throughCelite® filter aid and the filter cake washed thoroughly with hot THF.The filtrate was concentrated in vacuo. The residue was chromatographedon silica gel eluted with methylene chloride/methanol/ammonium hydroxide(89:9;1) to give 1.15 g (63% yield) of the title compound as a 1:1mixture of diastereomers; ¹ H NMR (CDCl₃) δ: 1.15-1.5 (m, 4H), 1.67 (m,1H), 1.90 (m, 1H), 2.20 (m, 1H), 2.35 (m, 1H), 2.45 (m, 1H), 2.55-3.05(m, 6H), 3.18 (m, 4H), 3.50 (m, 4H), 3.73 (s, 3H), 3.75 (m, 1H), 3.83(s, 3H), 3.87 (s, 6H), 6.80 (m, 2H), 6.92 (m, 2H), 7.2-7.4 (m, 10H).

Step 3:[1-2-trans]1-Aminomethyl-5,6-dihydroxy-2-(2'-hydroxy-1'-ethyl-3-phenyl-1,2,3,4-tetrahydronaphthaleneFormic Acid Salt

a stirred solution of1-aminomethyl-5,6-dimethoxy-2-(2'-hydroxy-1'-ethyl)-3-phenyl-1,2,3,4-tetrahydronaphthalene(0.6 g, 1.76 mmol, 1.0 equivalents), from Step 2, in 18 mL of anhydrousmethylene chloride cooled to -78° C., was added 3.52 mL of borontribromide (1M solution in methylene chloride, 3.52 mmol, 2.0equivalents). The resultant reaction mixture was stirred at -78° C. for1 h and then it was allowed to warm to ambient temperature. The reactionmixture was stirred at ambient temperature for 1 h and cooled again to-78° C. The reaction was quenched by the addition of 50 mL of anhydrousmethanol. The resultant solution was stirred at ambient temperature for1 h and then concentrated in vacuo. The residue was chromatographed onsilica gel eluted with ethyl acetate/formic acid/water (18:1:1 ) to givethe title compound as a light tan colored powder, m.p. 190° C. (dec);DCI MS M/Z: 312 (M+H)⁺ ; I.R. (KBr): 3400, 3240, 1600, 1490, 1290, 1050,700 cm⁻¹ ; ¹ H NMR (CD₃ OD) δ: 1.21 (m, 1H), 1.50 (m, 2H), 1.67 (m, 1H),2.15 (m, 1H), 2.22 (m, 1H), 2.53 (m, 1H), 2.63 (m, 1H), 3.10 (m, 8H),3.43 (m, 2H), 3.50 (m, 2H), 7.6 (m, 2H), 7.72 (m, 2H), 7.23 (m, 4H),7.35 (m, 6H), 8.51 (s, 2H). Analysis calculated for C₁₉ H₂₃ NO₃ +2.5HCO₂ H: C, 56.96; H, 6.37; N, 2.45. Found: C, 56.72; H, 6.08; N, 3.30.

EXAMPLE 46 1-Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene HydrochlorideStep 1:1-(N-t-Butoxycarbonyl)aminomethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthaleneHydrochloride

Triethylamine (0.33 mL, 2.37 mmol) was added to a cold solution of 1 g(2.58 mmol) of1-aminomethyl-5,6-bis(acetoxy)-3-phenyl-3,4-dihydronaphthalenehydrochloride, the product of Example 3, in 10 mL of DMF. The resultantsolution was added dropwise to a solution of 1.27 mL (5.52 mmol) oftrimethylacetic anhydride (commercially available from Aldrich ChemicalCo.) in 2 mL of DMF. The solution was allowed to stir at 0° C. forapproximately 0.5 h and then at ambient temperature for 3 h. Water (25mL) was added and the resultant mixture was extracted with ethylacetate. The combined organic layers were washed successively with 2×15mL of 1N aqueous hydrochloric acid solution, 2×15 mL of water and 15 mLof brine, dried over anhydrous magnesium sulfate and concentrated invacuo. The residue was purified by flash chromatography on silica geleluted with hexane/ethyl acetate (3:1) to give 0.84 g (72% yield) of thetitle compound; DCI MS M/Z: 469 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ: 1.45 (s,9H), 2.25 (s, 3H), 2.28 (s, 3H), 2.63-2.78 (m, 1H), 2.91-3.03 (m, 1H),3.63-3.74 (m, 1H), 4.08-4.34 (m, 2H), 4.65 (br s, 1H), 6.02 (d, 1H),7.05 (d, 1H), 7.22-7.37 (m, 6H).

Step 2:5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl)aminomethyl-3-phenylnaphthalene

To a solution of 1.59 g (3.52 mmol) of5,6-bis(acetoxy)-1-(N-t-butoxycarbonyl)aminomethyl-3-phenyl-3,4-dihydronaphthalene,from Step 1, in 50 mL of toluene was added 0.80 g (3.52 mmol) of2,3-dichloro-5,6-dicyano-1,4-benzoquinone as a solid. The reactionmixture was heated to 70° C. under a nitrogen atmosphere and allowed tostir overnight. After cooling the reaction mixture to ambienttemperature, the orange colored mixture was filtered through a bed ofCelite® filter aid. The filtrate was concentrated in vacuo. The residuewas taken up in 50 mL of methylene chloride and the methylene chloridesolution was washed with 2×25 mL of 1M aqueous phosphoric acid solution,2×25 mL of aqueous sodium bicarbonate solution, 25 mL of water and 25 mLof brine, dried over anhydrous sodium sulfate, filtered and concentratedin vacuo. The residue was purified on a silica gel column eluted with3:1 hexane/ethyl acetate to give 0.77 g (49% yield) of the titlecompound as a white solid; ¹ H NMR (CDCl₃) δ: 1.47 (s, 9H), 2.35 (s,3H), 2.47 (s, 3H), 4.81 (d, 2H), 4.89 (br s, 1H), 7.36-7.43 (m, 5H),7.64-7.71 (m, 2H), 7.94 (d, 1H), 8.01 (d, 1H).

Step 3: 5,6-Bis(acetoxy)-1-aminomethyl-3-phenylnaphthalene Hydrochloride

5,6-Bis(acetoxy)-1-(N-t-butoxycarbonyl)aminomethyl-3-phenylnaphthalene(300 mg, 0.67 mmol) from Step 2 was dissolved in 10 mL of dioxanesaturated with anhydrous hydrogen chloride. The resultant solution wasstirred for 2 h at ambient temperature and concentrated in vacuo. Thesolid residue was recrystallized from ethanol/hexane to give 130 mg (50%yield) of the title compound as a white solid; DCI MS M/Z: 350 (M+H)⁺,367 (M+NH₄)⁺ ; ¹ H NMR (d₆ -DMSO) δ: 2.36 (s, 3H), 2.51 (m, 3H+DMSO),4.65 (s, 2H), 7.44-7.51 (m, 1H), 7.54-7.61 (m, 3H), 7.78 (d, 2H), 8.07(s, 1H), 8.13-8.19 (m, 2H), 8.39 (br s, 3H).

Step 4: 1-Aminomethyl-5,6-dihydroxy-3-phenylnaphthalene Hydrochloride

5,6-Bis(acetoxy)-1-aminomethyl-3-phenylnaphthalene hydrochloride (130mg, 0.34 mmol) from Step 3 was dissolved in 10 mL of methanol saturatedwith hydrogen chloride. The resultant solution was stirred at ambienttemperature for 3 h and then concentrated in vacuo. The solid residuewas dissolved in a minimal amount of ethanol. The ethanol solution wasadded slowly to 30 mL of dry diethyl ether and the precipitate wascollected by filtration. The solid was dried at 60° C. in vacuo to give77 mg (76% yield) of the title compound as a white solid, m.p. 205°-212°C. (dec); DCI MS M/Z: 266 (M+H)⁺, 283 (M+NH₄)⁺ ; ¹ H NMR (d₆ -DMSO) δ:4.50 (d, 2H), 7.28 (d, 1H), 7.36-7.60 (m, 4H), 7.77 (s, 1H), 7.83 (d,2H), 8.35 (s, 1H), 8.49 (br s, 3H), 9.22 (br s, 1H), 9.60 (br s, 1H).

EXAMPLE 47[1.3-cis]-1-Bromomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranStep 1: Epoxide Synthesis

t-Butyl ethylene oxide, the epoxide used in the synthesis of[1,3-cis]1-bromomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran,is commercially available. Epoxides necessary for the synthesis of otherbenzopyran derivatives of the present invention which are notcommercially available were synthesized by either Method A, Method B orMethod C described below.

Method A: 1-Cyclohexyl Ethylene Oxide

Sodium hydride (4.5 g, 187.5 mmol) and trimethylsulfoxonium iodide(41.25 g, 187.5 mmol) were combined in a 3-neck flask equipped with amechanical stirrer and an addition funnel. Dimethyl sulfoxide (DMSO) wasadded slowly, over a 30 min period, until 200 mL had been added. Gas wasevolved throughout the addition. A solution of cyclohexanecarboxaldehyde (21.8 mL, 180 mmol) in 50 mL of DMSO was added dropwiseto the reaction mixture over a 15 min period. The reaction mixture washeated to 55° C. and stirred at 55° C. for 30 min. The reaction mixturewas cooled to ambient temperature and poured into 500 mL of water. Theaqueous solution was extracted with 3×100 mL of diethyl ether. Thecombined ether extracts were washed with water and brine, dried overanhydrous magnesium sulfate and concentrated in vacuo. The crude productwas distilled (44° C., 0.1 mm) to give 14 g (62% yield) of 1-cyclohexylethylene oxide as a clear colorless liquid.

Method B: 1-Benzyl Ethylene Oxide

A solution of m-chloroperbenzoic acid (mCPBA; 17 g, 0.1 mol) in 120 mLof methylene chloride was added (at ambient temperature) dropwise to asolution of allyl benzene (10 g, 85 mmol) in 200 mL of methylenechloride. After the reaction mixture was stirred for 5 h with amechanical stirrer, 5 additional grams of m-CPBA were added and thereaction mixture stirred for another 2 h. The reaction mixture was thendiluted with 200 mL of ether, washed with 2×100 mL of aqueous sodiumbisulfite solution, 1×100 mL of aqueous sodium bicarbonate solution and1×100 mL of brine. The organic solution was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by bulb-to-bulb distillation (60° C., 0.1 mm) to give 8.5 g(77% yield) of 1-benzyl ethylene oxide as a clear colorless liquid.

Method C: [1R]1(1-Adamantyl)ethylene Oxide

The title compound was prepared as described in Example 179, Steps 1-3,below.

Step 2:3,3-Dimethyl-1-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-2-butanol

n-Butyl lithium (12.6 mL of 2.5M solution in hexane, 32 mmol) was addedto a solution of spiro[1,3-benzodioxole)-2,1'-cyclohexane] (5 g, 26.3mmol), prepared as described by Boeckmann and Schill in ChemischeBerichte, 110:703 (1977), in 40 mL of THF at 0° C. After 4 h,3,3-dimethyl-1,2-epoxybutane (2.5 g, 25 mmol), commercially availablefrom Aldrich Chemical Company, was added dropwise and the reactionmixture was warmed to 25° C. After 3 h at 25° C., the reaction mixturewas poured into saturated aqueous ammonium 1.0 chloride solution andextracted with 3×75 mL of diethyl ether. The combined ether extractswere washed with 50 mL of aqueous ammonium chloride solution and 50 mLof brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. to an oil. The oil was purified on silica geleluted with 10% ethyl acetate in hexane to give 3.5 g (48% yield) of thetitle compound as a viscous oil. DCI MS: 308 (M+NH₄)⁺. ¹ H NMR (d₆-DMSO) δ: 0.89 (s, 9H), 1.4-1.9 (m, 10H), 2.27 (dd, 1H, J=14.4, 9.3 Hz),2.75 (dd, 1H, J=14.4, 3.0 Hz), 3.3 (m, 1H), 4.38 (d, 1H, J=6.3 Hz), 6.18(m, 3H).

Step 3A;[1,3,cis]-1-Bromomethyl-3--t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

Boron trifluoride etherate (2.88 mL, 23.5 mmol) was added dropwise to astirred solution of the product of Step 2 (3.4 g, 11.7 mmol) andbromoacetaldehyde dimethyl acetal (1.4 mL, 11.7 mmol) in 15 mL ofmethylene chloride at -25° C. The reaction mixture was allowed to warmto 0° C. After 1 h at 0° C., the reaction mixture was diluted with 20 mLof diethyl ether and poured into 50 mL of aqueous sodium carbonatesolution. The resultant mixture was extracted with 3×50 mL of diethylether. The combined ether extracts were washed with aqueous sodiumbicarbonate solution and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluted with 2.5% ethylacetate in hexane to give 2.85 g (61% yield) of the title compound as acolorless solid, m.p. 113°-114° C. DCI MS: 414 (M+NH₄)⁺. ¹ H NMR (CDCl₃)δ: 1.0 (s, 9H), 1.4-1.95 (m, 10H), 2.6 (m, 2H), 3.28 (dd, 1H, J=9.3, 5.4Hz), 3.52 (dd, 1H, J=1.25, 7.5 Hz), 3.85 (dd, 1H, J=11.25, 3.0 Hz), 4.87(m, 1H), 6.5 (d, 1H, J=9.0 Hz), 6.6 (d, 1H, J=9.0 Hz).

Alternate Step 3B:[1,3-cis]-1-(2-Bromoethyl)-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

The title compound was prepared following the procedure described inStep 3 above and using 3-bromopropionaldehyde dimethyl acetal instead ofbromoacetaldehyde dimethyl acetal.

EXAMPLE 48 [1,3-cis]1-Aminomethyl3-t-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran Hydrochloride Step1:[1,3-cis]1-Azidomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

Lithium azide (1.6 g, 31 mmol) was added to a solution of the product ofExample 47 (2.5 g, 6.35 mmol) in 12 mL of dimethylformamide (DMF) at 25°C. The reaction mixture was heated at 75° C. for 2 h then cooled andpoured into 50 mL of water. The aqueous solution was extracted with 3×50mL of diethyl ether. The combined ether extracts were washed with 50 mLof water, 50 mL of brine, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with 2.5% ethyl acetate in hexane togive 1.56 g (69% yield) of the title compound as a colorless syrup; MSDCI: 358 (M+H)⁺, 375 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ: 1.1 (s, 9H), 1.4-1.95(m, 10H), 2.6 (m, 2H), 3.3 (dd, 1H, J=8.7, 6.0 Hz), 3.42 (dd, 1H,J=13.5, 7.5 Hz), 3.52 (dd, 1H, J=13.5, 3.0 Hz), 4.9 (m, 1H), 6.42 (d,1H, J=9.0 Hz), 6.59 (d, 1H, J=9.0 Hz).

Step 2:[1,3-cis]1-Aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranHydrochloride

Lithium aluminum hydride (LAH) solution (4.2 mL of 1M solution in ether,4.2 mmol) was added dropwise to a solution of[1,3-cis]1-azidomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran(1.5 g, 4.2 mmol) in 25 mL of dry diethyl ether at 0° C. After 15 min,the reaction mixture was allowed to warm to 25° C. and was stirred at25° C. for 1 h. The reaction mixture was cooled to 0° C. and thereaction was quenched by the sequential addition of 0.16 mL of water,0.16 mL of 15% aqueous sodium hydroxide solution and 0.48 mL of water.The precipitate was removed by filtration and washed with ether. Thefiltrate was concentrated in vacuo. The crude amine product wasdissolved in 15 mL of diethyl ether and diethyl ether saturated withhydrogen chloride was added in excess. The solid was collected by vacuumfiltration, washed with diethyl ether and dried to give 1.48 g (96%yield) of the title compound as a colorless solid, m.p. 164°-167° C.;DCI MS: 332 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO) δ: 1.0 (s, 9H), 1.4-1.9 (m,10H), 2.6 (m, 2H), 2.9 (dd, 1H, J=14.7, 10.5 Hz), 3.2 (m, 2H), 3.5 (dd,1H, J=14.7, 3.0 Hz), 4.82 (br d, 1H, J=8 Hz), 6.7 (m, 2H), 7.9 (br s,2H).

Step 3:[1,3-cis]1-Aminomethyl-3-t-butyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyranHydrochloride

A solution of[1,3-cis]1-aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranhydrochloride, from Step 1, (1 g, 2.72 mmol) in 15 mL of ethanol wassaturated with anhydrous hydrogen chloride. The solution was heated toreflux temperature. After 2 h at reflux temperature, the solution wasconcentrated to approximately 2 mL. A solid was precipitated withdiethyl ether, filtered, washed with diethyl ether and dried in a vacuumoven at 80° C. to give 630 mg (81% yield) of the title compound as acolorless powder, m.p. 258° C.; IR 3200, 1620, 1490, 1300, 1060 cm⁻¹ ;DCI MS: 252 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO) δ: 1.0 (s, 9H), 2.38 (dd, 1H,J=16.5, 12 Hz), 2.63 (dd, 1H, J=16.5, 2.8 Hz), 2.85 (m, 1H), 3.22 (dd,1H, J=12.0, 4.2 Hz), 3.45 (m, 1H), 4.8 (br d, 1H, J=7.5 Hz), 6.5 (d, 1H,J=7.8 Hz), 6.65 (d, 1H, J=7.8 Hz), 7.9 (br s, 2H), 8.46 (br s, 1H), 9.22(br s, 1H). Analysis calculated for C₁₄ H₂₂ ClNO_(3:) C, 58.43; H, 7.70;N, 4.9. Found: C, 58.37; H, 7.69; N, 4.77.

EXAMPLES 49-106

Following the synthesis outlined in Examples 47 and 48, using theappropriate epoxide and the appropriate aldehyde diacetal, Examples49-106 were made as disclosed in Table 3. The structure of each wasconfirmed by melting point (m.p), elemental analysis and mass spectra asdesignated.

    TABLE 3      - Examples 49-106      Elemental Analysis      Ex. No. Compound* Epoxide** mp °C. MS*** C H N      49      ##STR24##      ##STR25##      146 272 c: 60.60f: 60.63 6.056.27 4.424.20     50      ##STR26##      ##STR27##      225 278 c: 61.24f: 61.23 7.717.83 4.464.34     51      ##STR28##      ##STR29##      204-6 224 c: 55.50f: 55.85 6.997.15 5.395.31     52      ##STR30##      ##STR31##      234 264 c: 60.10f: 60.20 7.407.53 4.674.63     53      ##STR32##      ##STR33##      220-1 332 c: 58.78f: 58.39 6.036.20 3.813.71     54****      ##STR34##      ##STR35##      158[alpha].sub.D = -116.5°(c = 0.405, 1N HCl) 272 c: 60.60f:     60.63 6.056.27 4.424.20     55      ##STR36##      ##STR37##      230 302 c: 60.45f: 60.34 5.976.04 4.154.02     56      ##STR38##      ##STR39##      205 378 c: 66.74f: 66.54 5.855.88 3.383.37     57      ##STR40##      ##STR41##      217 358 c: 64.03f: 63.90 7.167.18 3.563.51     *As the HCl salt unless indicated otherwise (FB = free base); all     compounds 1-3 unless indicated otherwise     **1 = commercially available, 2 = synthesized by method A of Example 47,     = synthesized by Method B of Example 47; 4 = synthesized by Method C of     Example 47.     ***DCI MS(M + H)+-     ****Prepared by the procedure described in Examples 47, 48 and old130     using(-)Bchlorodiidopinocamphorylborane    Elemental Analysis      Ex. No. Compound* Epoxide** mp °C. MS*** C H N      58      ##STR42##      ##STR43##      225 380 c: 49.00f: 49.03 4.604.65 3.363.33     59      ##STR44##      ##STR45##      250 330 c: 65.65f: 65.59 7.717.83 3.833.73     60      ##STR46##      ##STR47##      242 286 c: 63.45f: 63.32 6.266.30 4.354.27     61      ##STR48##      ##STR49##      215 300 c: 64.38f: 64.33 6.606.65 4.174.06     62      ##STR50##      ##STR51##      241 350 c: 49.70f: 49.77 4.434.44 3.623.58     63      ##STR52##      ##STR53##      162-3 358 c: 73.90f: 73.82 8.748.74 3.923.67     64      ##STR54##      ##STR55##      200 308 c: 62.87f: 62.80 8.798.69 4.074.03     65      ##STR56##      ##STR57##      193 336 c: 64.58f: 64.74 9.219.13 3.773.69     66      ##STR58##      ##STR59##      203 278 c: 60.08+ 1/3 H.sub.2      Of: 60.34 7.777.77 4.374.34     *As the HBr salt unless indicated otherwise (FB = free base); all     compounds 1-3 cis unless indicated otherwise     **1 = commercially available, 2 = synthesized by method A of Example 47,     = synthesized by Method B of Example 47; 4 = synthesized by Method C of     Example 47.     ***DCI MS(M + H)+-     ****Prepared by the procedure described in Examples 47, 48 and old130     using (-)Bchlorodiidopinocamphorylborane    Elemental Analysis      Ex. No. Compound* Epoxide** mp °C. MS*** C H N      67      ##STR60##      ##STR61##      240 224 c: 55.49f: 55.16 6.996.86 5.395.29     68      ##STR62##      ##STR63##      205 280 c: 59.71+ 1/3 H.sub.2      Of: 59.41 8.348.14 4.354.25                                   69      ##STR64##      ##STR65##      222 350 c: 49.70f: 50.19 4.434.49 3.623.60     70****      ##STR66##      ##STR67##      265 324 c: 58.53+ 1/4 H.sub.2      Of: 58.72 5.685.57 4.264.15                                   71      ##STR68##      ##STR69##      250 362 c: 69.43f: 69.17 6.086.22 3.523.41     72      ##STR70##      ##STR71##      259 280 c: 60.84f: 59.80 8.308.14 4.434.29     73      ##STR72##      ##STR73##      212 250 c: 57.04+ 1/2 H.sub.2      Of: 57.44 7.186.98 4.754.52                                   74      ##STR74##      ##STR75##      234 306 c:f: na     75      ##STR76##      ##STR77##      227 316 c: 59.91+ 1/2 H.sub.2      Of: 59.94 6.426.05 3.883.89     *As the HBr salt unless indicated otherwise (FB = free base); all     compounds 1-3 cis unless indicated otherwise     **1 = commercially available, 2 = synthesized by method A of Example 47,     = synthesized by Method B of Example 47; 4 = synthesized by Method C of     Example 47.     ***DCI MS(M + H)+-     ****the benzyl protecting group was removed by hydrogenolysis prior to     removal of the cyclohexylidene group from the catechol.    Elemental Analysis      Ex. No. Compound* Epoxide** mp °C. MS*** C H N      76      ##STR78##      ##STR79##      >250 306 c: 63.23f: 62.99 8.258.16 4.104.00     77      ##STR80##      ##STR81##      222 316 c: 60.88+ 1/2 H.sub.2      Of: 60.64 6.726.52 3.743.85                                   78      ##STR82##      ##STR83##      >230 278 c: 61.23f: 61.26 7.717.71 4.464.44     79      ##STR84##      ##STR85##      215 252 c: 58.43f: 58.38 7.717.58 4.874.77     80      ##STR86##      ##STR87##      257-9 398 c: 43.86+ 1/2 H.sub.2      Of: 43.73 4.033.93 3.203.15                                     81      ##STR88##      ##STR89##      233 357 c: 48.93f: 49.18 5.905.86 3.573.51     82      ##STR90##      ##STR91##      250-1(dec) 302 c: 60.44f: 60.23 5.976.01 4.156.01     83      ##STR92##      ##STR93##      257(dec) 316 c: 61.45f: 61.20 6.306.30 3.983.91     84      ##STR94##      ##STR95##      267-9 330 c: 62.77+ 1/2Et.sub.2 O +1 H.sub.2 Of: 62.56 8.388.02     3.323.15     85      ##STR96##      ##STR97##      145(dec) 330 c: 63.06+0.8 H.sub.2      Of: 63.25 7.857.73 3.683.35                                       86      ##STR98##      ##STR99##      210 330 c: 63.06f: 63.16 7.857.70 3.683.58     87      ##STR100##      ##STR101##      254(dec) 341 c: 56.46+0.76 HClf: 56.70 5.425.44 6.936.75     88      ##STR102##      ##STR103##      251-2 292 c: 62.28f: 62.75 7.997.83 4.274.21     89      ##STR104##      ##STR105##      235-6 252 c: 58.43f: 58.48 7.717.71 4.874.66     90      ##STR106##      ##STR107##      na 344 c: f: na     91      ##STR108##      ##STR109##      244-5(dec) 306 c: 62.42f: 62.71 8.298.20 4.044.08     92      ##STR110##      ##STR111##      >260(dec) 339 c: 50.07f: 49.95 6.306.10 7.307.30     93      ##STR112##      ##STR113##      239 278 c: 61.24f: 61.51 7.717.87 4.464.28     *As the HBr salt unless indicated otherwise (FB = free base); all     compounds 1-3 cis unless indicated otherwise     **1 = commercially available, 2 = synthesized by method A of Example 47,     = synthesized by Method B of Example 47; 4 = synthesized by Method C of     Example 47.     ***DCI MS(M + H)+-     ****Prepared by the procedure described in Examples 47, 48 and old130     using (-)Bchlorodiidopinocamphorylborane    Elemental Analysis      Ex. No. Compound* Epoxide** mp °C. MS*** C H N      94      ##STR114##      ##STR115##      228 292 c:f: na     95      ##STR116##      ##STR117##      >260 266 c: 55.72f: 56.06 6.686.78 4.644.63     96      ##STR118##      ##STR119##      171-4 272 c: 61.54+ 1/4 H.sub.2      Of: 61.74 5.976.23 4.484.15                                     97      ##STR120##      ##STR121##      na 402 c: 50.85+0.3 HClf: 50.74 4.564.22 3.123.50     98      ##STR122##      ##STR123##      >225(dec) 340 c: 52.01+0.4 HClf: 52.31 4.324.49 3.473.59      99      ##STR124##      ##STR125##      >220(dec) 340 c: 340.1167****f: 340.1161      100      ##STR126##      ##STR127##      255 252 c: 58.43f: 58.20 7.717.58 4.874.67     101      ##STR128##      ##STR129##      204(dec) 272 c: 57.46f: 56.18 6.685.93 5.154.92      102      ##STR130##      ##STR131##      268(dec) na c: 252.1601****f: 252.1600      103      ##STR132##      ##STR133##      211-4 348 c: 59.77+HCl + H.sub.2      Of: 59.77 7.276.89 3.493.54                                      104      ##STR134##      ##STR135##      197 266 c: 59.70f: 59.85 8.028.06 4.644.57     105      ##STR136##      ##STR137##      249-51 250 c:f: na     106      ##STR138##      ##STR139##      206-10 348 c: 58.46+HCl +1.5 H.sub.2      Of: 58.32 7.367.20 3.413.22     *As the HBr salt unless indicated otherwise (FB = free base); all     compounds 1-3 cis unless indicated otherwise     **1 = commercially available, 2 = synthesized by method A of Example 47,     = synthesized by Method B of Example 47; 4 = synthesized by Method C of     Example 47.     ***DCI MS(M + H)+-     ****Prepared by the procedure described in Examples 47, 48 and old130     using (-)Bchlorodiidopinocamphorylborane;     ****High resolution mass spectrometry.

EXAMPLE 1071-Aminomethyl-8-bromo-adamantyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyranHydrobromide

Starting with the compound of Example 59, protecting the amino groupwith BOC and reacting 2.00 g (4.66 mmol) of the BOC-protected compoundwith 0.746 g (4.66 mmol) of bromine in methylene chloride at 0° C. for 3hours, followed by quenching with sodium lo bisulfite, extraction withmethylene chloride and purification by chromatography on silica gel, thetitle compound was prepared. mp 210° C. (dec). anal. calc. for C₂₀ H₂₆BrNO₃.0.8HBr.O.5EtOH: C, 50.83; H, 5.99: N, 2.85; found: C, 51.03; H,6.22; N, 2.76.

EXAMPLE 108[1,3-cis]1-(1S-(1-Amino)ethyl)-5,6-dihydroxy-3-phenyl-3,4-dihydro-1H-2-benzopyran

Following the synthesis outlined in Example 47, replacing thebromoacetaldehyde dimethyl ketal with N-Cbz-alaninal, the compound ofExample 108 was prepared. mp 272°-4° C. MS: 286. anal. calc.+HCl+H₂ O:C, 60.09; H, 6.50: N, 4.12; found: C, 60.34; H, 6.32; N, 4.01.

EXAMPLE 109[1,3-cis]1-Aminomethyl-5,6,dihydroxy-3-(2'-tetrahydrofuranyl)-3,4-benzopyranHydrobromide Step 1:1-(2',3'-Dimethoxyphenyl)-N-methoxy-N-methyl-acetamide

Oxalyl chloride (0.45, 5.1 mmol) and 2-3 drops of N,N-dimethylformamide(DMF) were added to a chilled (0° C.) solution of2,3-dimethoxyphenylacetic acid in 25 mL of THF. The resultant solutionwas allowed to warm to ambient temperature over a 4 h period. Thesolvent was removed in vacuo and the residue was dissolved in 50 mL ofchloroform. N-methoxy-N-methyl-hydroxylamine hydrochloride (0.55 g, 5.61mmol) was added and the resultant solution was chilled to 0° C. Pyridine(0.91 mL, 11.23 mmol) was added and the solution was stirred for 2 h at0° C. The solution was then washed twice with brine, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to anoil. The oil was purified by column chromatography on silica gel elutedwith 20% ethyl acetate in hexane to give 0.65 g (53% yield) of the titlecompound as an oil; MS DCI: 240 (M+H)⁺, 257 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃)δ: 3.21 (s, 3H), 3.68 (s, 3H), 3.80-3.84 (m, 5H), 3.87 (s, 3H),6.80-6.87 (m, 2H), 6.98-7.4 (m, 1H).

Step 2: 2-(2',3'-Dimethoxyphenyl-1-furanylethanone

n-Butyl lithium (1.87 mL, 3.76 mmol of a 1.75M solution in hexanes) wasadded to a chilled (0° C.) solution of furan (0.2 mL, 2.72 mmol) in 5 mLof THF. The mixture was allowed to warm to ambient temperature over a 4h period. The mixture was then chilled again to 0° C. and a solution of0.65 g (2.72 mmol) of1-(2',3'-dimethoxyphenyl)-N-methoxy-N-methylacetamide, from Step 1, wasadded. The reaction mixture was allowed to warm to ambient temperatureover a 2 h period and was then quenched with a saturated aqueousammonium chloride solution. The mixture was extracted with ethyl acetateand the extracts were washed once each with saturated aqueous ammoniumchloride and brine. The extracts were dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 0.5 g (75% yield) ofthe title compound as an oil; MS DCI: 247 (M+H)⁺, 264 (M+NH₄)⁺ ; ¹ H NMR(CDCl₃)δ: 3.80 (s, 3H), 3.85 (s, 3H), 4.15 (s, 2H), 6.51-6.53 (m, 1H),6.82-6.88 (m, 3H), 6.99-7.05 (m, 1H), 7.25-7.28 (m, 1H).

Step 3: 2-(2',3'-Dimethoxyphenyl)-1-tetrahydrofuranyl Ethanol

A solution of 450 mg(1.8 mmol) of2-(2',3'-dimethoxyphenyl)-1-furanylethanone, from Step 2, and 20%palladium on carbon (225 mg) in 75 mL of methanol was shaken under 4atmospheres of hydrogen until hydrogen uptake ceased. The solution wasfiltered and concentrated in vacuo to give 320 mg (69% yield) of thetitle compound as an oily solid. This product was carried on withoutpurification to the next step.

Step 4:1-Aminomethyl-3-(2'-tetrahydrofuranyl)-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyran Hydrobromide

2-(2',3'-Dimethoxyphenyl)-1-tetrahydrofuranyl ethanol, from Step 3, wasconverted to the title compound using the procedures described in Step 3of Example 47 and Steps 1 and 2 of Example 48. The dimethoxy protectinggroups were removed with boron tribromide by the procedures described inStep 3 of Example 2 to afford the title compound, m.p. >250° C.; FAB MS(M/Z): 266 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO) δ: 1.75-1.93 (m, 4H), 2.37-2.47(m, 1H), 2.50-2.60 (m, 1H), 2.60-2.68 (m, 1H), 2.71-2.79 (m, 1H),3.65-3.72 (m, 1H), 3.76-3.84 (m, 2H), 3.90-4.00 (m, 1H), 4.84-4.91 (m,1H), 6.48 (d, 1H), 6.68 (d, 1H), 7.72-7.84 (m, 2H), 8.41-8.49 (m, 1H),9.20-9.28 (m, 1H). High resolution mass spectral analysis calculated forC₁₄ H₂₀ NO₄ : 266.132. Found: 266.1391

EXAMPLE 110[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-(3'-prop-1'-ynyl)-3,4-dihydro-1H-2-benzopyranHydrochloride Step 1:3-(Spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-propene Oxide

n-Butyl lithium (30 mL of 2.5M solution in hexane, 75 mmol) was addeddropwise to a solution of spiro[1,3-benzodioxole)-2,1'-cyclohexane] (5g, 26.3 mmol), prepared as described by Boeckmann and Schill inChemische Berichte 110:703 (1977), in 125 mL of anhydrous THF at 0° C.The solution was stirred at 0° C. for 2 h and then a solution of 4.8 g(52 mmol) of epichlorohydrin in 10 mL of THF was added via cannula overa 15 minute period. The reaction mixture was heated to ambienttemperature and stirred for 60 minutes at ambient temperature and heatedat 65° C. for 75 minutes. The reaction mixture was cooled to ambienttemperature and poured into 150 mL of water. The aqueous layer wasextracted with 2×75 mL of diethyl ether. The combined ether layers werewashed with 75 mL of saturated sodium bicarbonate and brine, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to anamber colored oil. The oil was purified by flash chromatography onsilica gel eluted with 8% ethyl acetate in hexane to give 6.81 g (53%yield) of the title compound as a clear oil.

Step 2: 1-(Spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-4-pentyn-2-ol

Crude 3-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-propene oxide(8.29 g, 33.7 mmol), from Step 1, was added to a chilled (0° C.)suspension of lithium acetylideethylenediamine complex (4.65 g, 45.5mmol of a 90% solid) in 50 mL of methyl sulfoxide. The mixture wasallowed to warm to ambient temperature over a 3 h period during whichthe mixture became a homogeneous solution. The reaction was quenchedwith 50 mL of water and the aqueous layers were washed with water andbrine, dried over anhydrous magnesium sulfate, filtered and concentratedin vacuo to an oil. The oil was purified by column chromatography onsilica gel eluted with 15% ethyl acetate in hexane to give 2.08 g (23%yield) of the title compound as an oil; MS DCI: 273 (M+H)⁺, 290 (M+NH₄)⁺; ¹ H NMR (CDCl₃) δ: 1.45-1.55 (m, 2H), 1.67-1.77 (m, 4H), 1.85-1.95 (m,4H), 2.09 (t, 1H), 2.28 (d, 1H), 2.32-2.50 (m, 2H), 2.80-2.93 (m, 2H),4.00-4.15 (m, 1H), 6.62-6.77 (m, 3H).

Step 3:1-Aminomethyl-5,6-dihydroxy-3-(3'-prop-1'-ynyl)-3,4-dihydro-1H-2-benzopyranHydrochloride

1-(Spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-4-pentyn-2-ol, from Step2, was converted to the title compound using the procedures described inStep 3 of Example 47 and Steps 1-3 of Example 48 to afford the titlecompound, m.p. >250° C.; DCI MS (M/Z): 234 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO)δ: 2.34-2.47 (m, 1H), 2.52-2.57 (m, 1H), 2.57-2.68 (m, 1H), 2.84-2.92(m, 2H), 2.95 (t, 1H), 3.39-3.47 (m, 1H), 3.71-3.81 (m, 1H), 4.87-4.91(m, 1H), 6.2 (d, 1H), 6.69 (d, 1H), 7.88 (s, 2H), 8.53 (s, 1H), 9.31 (s,1H). Analysis calculated for C₁₃ H₁₆ ClNO₃ : C, 57.89; H, 5.98; N, 5.19.Found: C, 57.73; H, 6.15; N, 5.09.

EXAMPLE 111[1,3-cis]3-Cyclohexyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyranHydrochloride

[1,3-cis]-1-Aminomethyl-3-cyclohexyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranhydrochloride (synthesized as described in Steps 1 and 2 of Example 48for[1,3-cis]-1-aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranhydrochloride) (0.82 g, 2.3 mmol) was partitioned between methylenechloride and saturated aqueous sodium bicarbonate solution. Themethylene chloride layer was concentrated under reduced pressure and theresidue was dissolved in 25 mL of ethyl formate. The ethyl formatesolution was heated to reflux temperature. After 1 h at refluxtemperature, the reaction mixture was concentrated to a white solid. Thesolid was dissolved in 15 mL of THF and 175 mg (4.6 mmol) of lithiumaluminum hydride (LAH) was added. The reaction mixture was heated atreflux temperature for 3 h then cooled to 0° C. The reaction wasquenched by the sequential addition of 0.175 mL of water, 0.175 mL of15% aqueous sodium hydroxide solution and 0.525 mL of water. Thereaction mixture was filtered and the filter cake washed with diethylether. The filtrate was concentrated in vacuo. The residue was dissolvedin 20 mL of ethanol and the alcohol solution was saturated withanhydrous hydrogen chloride then heated at reflux temperature for 2 h.The ethanol was evaporated down to approximately 2 mL and ether wasadded until a solid precipitate was formed. The solid was filtered,washed with diethyl ether and dried to give 504 mg (67% yield) of thetitle compound as a colorless powder, m.p. 244° C.; DCI MS: 292 (M+H)⁺.Analysis calculated for C₁₇ H₂₆ ClNO₃ : C, 62.28; H, 7.99; N, 4.27.Found: C, 62.24; H, 7.90; N, 4.21.

EXAMPLE 112[1R,3S]3-Butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyranHydrochloride

Following the synthesis outlined in Example 111 and starting with[1R,3S]1-aminomethyl-3-t-butyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranhydrochloride from Step 2 of Example 48,[1R,3S]3-t-butyl-5,6-dihydroxy-1-methylaminomethyl-3,4-dihydro-1H-2-benzopyranhydrochloride was prepared, m.p. 246° C.; DCI MS: 266 (M+H)⁺. Analysiscalculated for C₁₅ H₂₃ ClNO₃ : C,59.70; H, 8.00; N, 4.64. Found: C,59.64; H, 8.10; N, 4.45.

EXAMPLE 113[1,3-cis]1-(N-Allyl)aminomethyl-3-cyclohexyl-5,6-dihydroxy-3,4-dihydro-1H-2-benzopyranHydrochloride Step 1:[1,3-cis]1-(N-Allyl)aminomethyl-3-cyclohexyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

[1,3-cis]1-Bromomethyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran(1.1 g, 2.6 mmol) (prepared as described in Example 47, using cyclohexylethylene oxide) and dissolved in 10 mL of allyl amine. The reactionmixture was heated at reflux temperature for 5 h then concentrated invacuo. The residue was dissolved in 50 mL of ethyl acetate. The solutionwas washed with 2×25 mL of aqueous sodium bicarbonate solution and 1×25mL of brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluted with 30% ethyl acetate in hexane to give 928 mg(90% yield) of the title compound as a colorless oil; DCI MS: 398 (M+H)⁺; ¹ H NMR (CDCl₃) δ: 1.0 (m, 20H), 2.05 (br d, 1H, J=11.0 Hz), 2.4 (brs, 1H), 2.5 (dd, 1H, J=13.5, 9.0 Hz), 2.7 (dd, 1H, J=13.5, 2.8 Hz), 2.82(dd, 1H, J=10.0, 7.5 Hz), 3.18 (dd, 1H, J=10.0, 3.0 Hz), 3.48 (m, 3H),4.7 (br d, 1H, J=7.5 Hz), 5.2 (m, 2H), 5.95 (m, 1H), 6.5 (d, 1H, J=6.3Hz), 6.58 (d, 1H, J=6.3 Hz).

Step 2:[1,3-cis]1-(N-Allyl)aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranHydrochloride

[1,3-cis]1-(N-Allyl)aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-cyclohexylidenedioxy-1H-2-benzopyran(920 mg, 2.3 mmol), from Step 1, was dissolved in 15 mL of lo ethanolsaturated with anhydrous hydrogen chloride. The acidic solution washeated at reflux temperature for 2 h then concentrated to ˜2 mL. Diethylether was added and the precipitate was filtered, washed with diethylether and dried to give 590 mg (72% yield) of the title compound as anoff-white powder, m.p. 217°-219° C.; DCI MS: 318 (M+H)⁺. Analysiscalculated for C₁₉ H₂₈ ClNO₃ : C, 64.49; H, 7.98; N, 3.96. Found: C,64.34; H, 8.02; N, 3.82.

EXAMPLES 114-148

Following the syntheses described in Examples 47 and 113, using theappropriate epoxide and the appropriate amine, Examples 114-131 wereprepared as disclosed in Table 4.

Examples 123, 124 and 127 were prepared by replacing thebromoacetaldehyde dimethyl acetal of Example 47 step 3 with theappropriate Z-protected prolinal dimethyl acetal as indicated, followedby deprotection. The chiral prolinals were prepared from the chiralamino acid alcohols following the procedures given in Chem. Pharm. Bull(1982), 30, 1921 and Tetrahedron Letters (1986), 27, 6111.

Examples 132-146 were prepared by the procedures described in Examples47, 48 and 111. Examples 147 and 148 were prepared were prepared by theprocedures described in Examples 47, 48 and 111, repeating the procedureof Example 111 in order to place the second methyl group on the aminofunction. The structure of each was confirmed by melting point, massspectra and elemental analysis as designated.

                                      TABLE 4                                     __________________________________________________________________________                                                                         1        Examples 114-148                                                                                                                  Elemental Analysis        Ex. No.                                                                             Compound*                 Amine     mp ° C.                                                                     MS** C    H  N                 __________________________________________________________________________    114                                                                                  ##STR140##                                                                                              ##STR141##                                                                             200  318  c: 64.49 f:64.43                                                                   7.97 8.02                                                                        3.96 3.88         115                                                                                  ##STR142##                                                                                              ##STR143##                                                                             240-2                                                                              332  c: 65.29 f:65.26                                                                   8.22 8.26                                                                        3.81 3.73         116                                                                                  ##STR144##                                                                                              ##STR145##                                                                             116  336  c: 59.91 + 1/2                                                                H.sub.2 O f:60.13                                                                  8.20 8.02                                                                        3.67 3.61         117                                                                                  ##STR146##                                                                                              ##STR147##                                                                             225  370  c: 68.05 f:68.00                                                                   7.95 7.91                                                                        3.45 3.36         118                                                                                  ##STR148##                                                                                              ##STR149##                                                                             211-2                                                                              316  c: 64.86 f:64.58                                                                   7.45 7.59                                                                        3.98 3.82         119                                                                                  ##STR150##                                                                                              ##STR151##                                                                             216-8                                                                              330  c: 64.85 f:65.13                                                                   7.75 7.68                                                                        3.78 3.72         120                                                                                  ##STR152##                                                                                              ##STR153##                                                                             172-3                                                                              332  c: 65.29 f:65.35                                                                   8.22 8.36                                                                        3.81 3.77         121                                                                                  ##STR154##                                                                                              ##STR155##                                                                             144-6                                                                              334  c: 69.94 f:64.68                                                                   8.72 8.70                                                                        3.79 3.73         122                                                                                  ##STR156##                                                                                              ##STR157##                                                                             141-2                                                                              332  c: 65.29 f:65.22                                                                   8.22 8.17                                                                        3.81 3.79         123                                                                                  ##STR158##                                                                                              ##STR159##                                                                             248-50 (dec)                                                                       312  c: 63.15 f:63.29                                                                   6.56 6.16                                                                        3.88 3.87         124                                                                                  ##STR160##                                                                                              ##STR161##                                                                             242-4                                                                              312  c: 65.61 +1 HCl                                                               f:65.21                                                                            6.38 6.48                                                                        4.03 3.95         125                                                                                  ##STR162##                                                                                              ##STR163##                                                                             152-5                                                                              292  c: 62.47 f:62.43                                                                   7.71 8.04                                                                        4.29 4.24         126                                                                                  ##STR164##                                                                                              ##STR165##                                                                             215-222 (dec)                                                                      312  c: 60.53 +0.8 HCl                                                             f:60.43                                                                            6.10 5.89                                                                        3.72 3.66         127                                                                                  ##STR166##                                                                                              ##STR167##                                                                             220 (dec)                                                                          312  c: 62.97 +0.4 HCl                                                             f:62.89                                                                            6.23 6.10                                                                        3.87 3.85         128                                                                                  ##STR168##                                                                                              ##STR169##                                                                             123  280  c: 60.85 f:60.85                                                                   8.30 8.31                                                                        4.44 4.36         129                                                                                  ##STR170##                                                                                              ##STR171##                                                                             165  292  c: 61.94 +0.1 H.sub.2                                                         O f:61.78                                                                          8.01 8.05                                                                        4.25 4.20         130                                                                                  ##STR172##                                                                                              ##STR173##                                                                             180-83                                                                             312  c: 64.93 +0.1 HCl                                                             f:64.68                                                                            6.34 6.33                                                                        3.98 3.98         131                                                                                  ##STR174##                                                                                              ##STR175##                                                                             118  374  c: 61.90 f:62.24                                                                   8.56 8.34                                                                        4.27 4.24         132                                                                                  ##STR176##                         221  264  c: 59.03 +0.3 H.sub.2                                                         O f:59.20                                                                          7.46 7.32                                                                        4.59 7.49         133                                                                                  ##STR177##                         >260 239  c: 46.31 f:46.04                                                                   6.48 6.03                                                                        9.00 8.08         134                                                                                  ##STR178##                         264  344  c: 66.39 f:66.31                                                                   7.96 7.94                                                                        3.69 3.57         135                                                                                  ##STR179##                         194-6                                                                              266  c: 59.69 f:59.24                                                                   8.02 7.94                                                                        4.64 4.46         136                                                                                  ##STR180##                         >260 304  c: 57.07 f:56.79                                                                   5.92 5.73                                                                        3.92 3.61         137                                                                                  ##STR181##                         >260 (dec)                                                                         330  c: 59.45 f:59.25                                                                   6.83 6.43                                                                        3.65 3.56         138                                                                                  ##STR182##                         250-2                                                                              286  c: 63.40 f:63.00                                                                   6.30 6.30                                                                        4.40 4.30         139                                                                                  ##STR183##                         na   3.58 c: 66.25 +0.5 EtOH                                                            f:66.30                                                                            8.46 8.39                                                                        3.36 3.36         140                                                                                  ##STR184##                         209-10                                                                             306  c: 63.24 f:62.97                                                                   8.25 8.17                                                                        4.10 4.02         141                                                                                  ##STR185##                         145  292  c: 62.28 f:62.16                                                                   7.99 7.84                                                                        4.27 4.26         142                                                                                  ##STR186##                         194  306  c: 306.2069***                                                                f:306.2076                143                                                                                  ##STR187##                         247  280  c: 57.05 f:56.72                                                                   7.02 6.84                                                                        4.44 4.30         144                                                                                  ##STR188##                         na   280  c: 60.85 f:60.74                                                                   8.30 8.13                                                                        4.44 4.43         145                                                                                  ##STR189##                         >250 362  c: 58.07 +2 HCl                                                               f:57.71                                                                            6.96 7.18                                                                        3.22 2.92         146                                                                                  ##STR190##                         185  280  c: 60.85 f:61.14                                                                   8.30 8.14                                                                        4.44 4.24         147                                                                                  ##STR191##                         223  280  c: 60.85 f:60.65                                                                   8.30 8.21                                                                        4.44 4.33         148                                                                                  ##STR192##                         dec  358  c: f:                                                                               na                  148A                                                                                 ##STR193##                         215  320  c: 64.12 f:63.95                                                                   8.50 8.48                                                                        3.94 3.84         __________________________________________________________________________     *As the HCl salt unless indicated otherwise (FB = free base); Adam =          adamantyl; all compounds 1-3 cis unless indicated otherwise                   ***DCl MS (M + H)+-                                                           ***High Resolution mass spectrometry                                     

EXAMPLE 1495,6-Dihydroxy-1-(N-methyl)aminomethyl-3-phenyl-3,4,-dihydronaphthalene

1-Aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, the productof Step 2 of Example 2, was N-methylated as described in Example 111 anddeprotected as described in Step 4 of Example 2 to give the titlecompound as its hydrochloride salt, m.p. 131°-133° C.; DCI MS: 282(M+H)⁺. Analysis calculated for C₁₈ H₂₀ ClNO₂ : C, 68.03; H, 6.34; N,4.41. Found: C, 67.64; H, 6.54; N, 4.31.

EXAMPLE 150[1,3-cis]5,6,Dihydroxy-1-(N-methyl)aminomethyl-3-phenyl-1,2,3,4-tetrahydro-naphthalene

[1,3-cis]1-Aminomethyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalene,the product of Step 1 of Example 35, was N-methylated as described inExample 111 and deprotected as described in Step 4 of Example 2 to givethe title compound as its hydrochloride salt, m.p. 211°-213° C.; DCI MS:284 (M+H)⁺. Analysis calculated for C₁₈ H₂₂ ClNO₂ : C, 65.75; H, 7.05;N, 4.26. Found: C, 65.54; H, 6.89; N, 4.04.

EXAMPLES 151-153

Following the synthesis described in Examples 1A and 2, the1-aminomethyl precursors to Examples 151-153 were prepared with thecatechol hydroxyl groups protected as dimethyl ethers. The 1-aminomethylcompounds were N-acylated. The N-acyl derivatives reduced as describedin Example 111 and deprotected as described in Step 4 of Example 2,using the appropriate acylating agent and lithium aluminum hydride (LAH)as the reducing agent to give Examples 151-153 as their hydrochloridesalts unless otherwise noted. In the case of Example 152, theacylation/reduction sequence was repeated to give the dialkylaminoderivative. Examples 151-153 are disclosed in Table 5. The structure ofeach was confirmed by melting point (m.p.), elemental analysis and massspectra, as designated.

                                      TABLE 5                                     __________________________________________________________________________    Examples 151-153                                                                                                      High                                                                          Resolution                                                                    Mass                                  Ex. No.                                                                            Compound*           Acyl chloride                                                                        mp °C.                                                                     MS**                                                                              Spectrum                              __________________________________________________________________________    151                                                                                 ##STR194##                                                                                        ##STR195##                                                                          198 310 c: 309.1725 f: 309.1722               152                                                                                 ##STR196##                                                                                        ##STR197##                                                                          na  352 c: 351.2196 f: 351.2203                    MeSO.sub.4.sup.-  salt                                                   153                                                                                 ##STR198##                                                                                        ##STR199##                                                                          122 296 c: 295.1572 f: 295.1571               __________________________________________________________________________     *As the HCl salt unless indicated otherwise (FB = free base); all             compounds 1-3 cis unless indicated otherwise                                  ***DCl MS (M + H)+-                                                           ***High Resolution mass spectrometry                                     

EXAMPLE 154[1,3-cis]1,3-Bis(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranDihydrochloride Step 1:1-Benzyloxy-3-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-2-propanol

Glycidol (3.1 g, 42 mmol) was added dropwise to a suspension of sodiumhydride (1.0 g, 42 mmol) in 25 mL of dry dimethyl formamide (DMF) at 0°C. After stirring the suspension for 30 min at 0° C., 7.1 g (42 mmol) ofbenzyl bromide was added dropwise and the reaction mixture was stirredat 0° C. for 40 min. The reaction mixture was then diluted with 75 mL ofdiethyl ether, transferred to a separatory funnel and washed with 2×30mL of 2N aqueous sulfuric acid solution, 2×30 mL of water and saturatedaqueous sodium bicarbonate solution. The organic solution was dried overanhydrous magnesium sulfate, filtered and concentrated at reducedpressure to give 5.3 g of the protected epoxy alcohol as an oil.

N-Butyl lithium (18.5 mL of 2.5M solution in hexane, 46 mmol) was addedto a solution of spiro[(1,3-benzodioxole)-2,1'-cyclohexane](7.4 g, 39mmol) in 75 mL of THF at 0° C. After 4 h, the protected glycidol (5.3 g,32 mmol) in 10 mL of THF was added dropwise and the reaction mixture wasallowed to warm to ambient temperature. After 1.5 h, the reactionmixture was poured into 10% aqueous ammonium chloride solution andextracted with 2×50 mL of diethyl ether. The combined ether extractswere Washed with ammonium chloride solution, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel eluted with 20% ethylacetate in hexane to give 4.4 g (38% yield) of the title compound as acolorless oil. DCI MS: 372 (M+NH₄)⁺, 355 (M+H)⁺. ¹ H NMR (CDCl₃) δ:1.4-1.9 (m, 10H), 2.46 (d, 1H, J=3.9 Hz), 2.79 (d, 2H, J=7.0 Hz), 3.4(dd, 1H, J=9.9, 7.2 Hz), 3.52 (dd, 1H, J=9.9, 3.0 Hz), 4.12 (m, 1H),4.54 (s, 2H), 6.6-6.73 (m, 3H), 7.34 (m, 5H).

Step 2:[1,3-cis]3-Benzoxymethyl-1-bromomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

A solution of1-benzyloxy-3-(spira-[(1,3-benzodioxole)-2,1'-cyclohexane])-2-propanol(4.3 g, 12 mmol), from Step 1, and bromoacetaldehyde dimethyl acetal(1.7 mL, 14 mmol) in 25 mL of methylene chloride was cooled to 0° C.Boron trifluoride etherate (3.6 mL, 29 mmol) was added dropwise and thereaction mixture was stirred for 1.5 h. The resultant dark brownsolution was poured into 50 mL of 10% aqueous sodium carbonate solutionand the aqueous solution was extracted with 3×50 mL of diethyl ether.The combined ether extracts were washed with saturated aqueous sodiumbicarbonate solution and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluted with 20% ethylacetate in hexane to give 4.2 g (75%) of the title compound as acolorless syrup; DCI MS: 476 (M+NH₄)⁺. ¹ H NMR (CDCl₃) δ: 1.45-1.95 (m,10H), 2.57 (dd, 1H, J=16.5, 11.4 Hz), 2.71 (dd, 1H, J=16.5, 3 Hz), 3.59(dd, 1H, J=11.4, 6 Hz), 3.63 (dd, 1H, J=10.8, 4.2 Hz), 3.73 (dd, 1H,J=10.8, 6 Hz), 3.87 (dd, 1H, J=11.4, 2.7), 4.65 (d, 1H, J=12 Hz), 4.72(d, 1H, J=12 Hz), 5.0 (m, 1H), 6.52 (d, 1H, J=8.4 Hz), 6.62 (d, 1H,J=8.4 Hz), 7.42-7.25 (m, 5H).

Step 3:[1,3-cis]1-Bromomethyl-3-hydroxymethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

5% Platinum on carbon (1.0 g) was added to a solution of[1,3-cis]3-benzyloxymethyl-1-bromomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran(4.0 g, 8.7 mmol), from Step 2, in 150 mL of methanol and 5 mL of ethylacetate. The reaction mixture was sealed under 4 atmospheres of hydrogenand shaken overnight. The reaction mixture was filtered to remove thecatalyst and concentrated to a light brown oil. The oil was purified bycolumn chromatography on silica gel eluted with 30% ethyl acetate inhexane to give 2.2 g (68% yield) of the title compound as a white foam.¹ H NMR (CDCl₃) δ: 1.4-1.95 (m, 10H), 2.25 (dd, 1H, J=8.4, 4.5 Hz), 2.62(d, 2H, J=7.5 Hz), 3.57 (dd, 1H, J=11.4, 6.9 Hz), 3.65-3.9 (m, 4H), 4.98(m, 1H), 6.52 (d, 1H, J=8.4 Hz), 6.63 (d, 1H, J=8.4 Hz).

Step 4:1-Azidomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1H-2-benzopyran

Lithium azide (1.0 g, 20 mmol) was added to a solution of[1,3-cis]1-bromomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1H-2-benzopyran(2.17 g, 5.87 mmol), from Step 3, in 20 mL of DMF. The reaction mixturewas heated to 70° C. for 1.5 h then cooled to ambient temperature andpoured into 50 mL of diethyl ether and 50 mL of water. The layers wereseparated and the aqueous layer was extracted with 2×50 mL of diethylether. The combined ether layers were washed with saturated aqueoussodium bicarbonate solution, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with 25% ethyl acetate in hexane togive 1.38 g (70% yield) of the title compound as a colorless glass. ¹ HNMR (CDCl₃) δ: 1.45-1.95 (m, 10H), 2.14 (dd, 1H, J=9.0, 4.8 Hz), 2.63(d, 2H, 7.5 Hz), 3.5 (dd, 1H, J=13.5, 7.0 Hz), 3.62 (dd, 1H, J=13.5, 2.7Hz), 3.65-3.9 (m, 3H), 5.02 (m, 1H), 6.45 (d, 1H, J=8.4 Hz), 6.61 (d,1H, J=8.4 Hz).

Step 5:[1,3-cis]1,3-Bis(azidomethyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

Methanesulfonyl chloride (0.128 mL, 1.65 mmol) was added dropwise to asolution of 1,3-cis1-azidomethyl-5,6-cyclohexylidenedioxy-3-hydroxymethyl-3,4-dihydro-1H-2-benzopyran(500 mg, 1.5 mmol), from Step 4, and 0.314 mL (2.25 mmol) oftriethylamine (TEA) in 15 mL of methylene chloride at 0° C. Afterstirring for 30 min at 0° C., the reaction mixture was transferred to aseparatory funnel and diluted with diethyl ether. The layers wereseparated and the organic layer was washed with 2×20 mL of water, 2×15mL of 1N aqueous hydrochloric acid solution and brine, dried overmagnesium sulfate, filtered and concentrated under reduced pressure toyield a white foam. The foam was dissolved in 20 mL of DMF and 440 mg (9mmol) of lithium azide was added. The reaction mixture was heated to 80°C. and stirred at 80° C. for 4 h then cooled and poured into 50 mL ofwater. The aqueous solution was extracted with 3×30 mL of diethyl etherand the combined ether extracts were washed with 30 mL of water andbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified on silica gel eluted withdiethyl ether to give 450 mg (84% yield) of the title compound as a paleyellow oil; DCI MS: 374 (M+NH₄)⁺. ¹ H NMR (CDCl₃) δ: 1.45-1.95 (m, 10H),2.67 (m, 2H), 3.38 (dd, 1H, J=13.5, 3.9 Hz), 3.5 (m, 2H), 3.7 (dd, 1H,J=13.5, 2.7 Hz), 3.9 (m, 1H), 5.0 (m, 1H), 6.47 (d, 1H, J=8.7 Hz), 6.62(d, 1H, J=8.7 Hz).

Step 6:[1,3-cis]1,3-Bis(aminomethyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

Lithium aluminum hydride (2.4 mL of 1.0M solution in diethyl ether, 2.4mmol) was added dropwise to a solution of [1,3-cis]1,3-bis(azidomethyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran(430 mg, 1.2 mmol), from Step 5, in 10 mL of anhydrous diethyl ether at0° C. The reaction mixture was allowed to warm to ambient temperatureand stirred for 45 min. The reaction was then quenched by the sequentialaddition of 91 μL of water, 91 μL of 15% aqueous sodium hydroxidesolution and 273 μL of water. The solution was dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo to give 212 mg(85% yield) of the title compound as a colorless glass; ¹ H NMR (CDCl₃)δ: 1.4-1.95 (m, 14H), 2.5 (dd, 1H, J=17.1 Hz), 2.65 (dd, 1H, J=17.1, 3Hz), 2.9 (m, 2H), 3.0 (dd, 1H, J=13.8, 6 Hz), 3.21 (dd, 1H, J=13.8, 2.4Hz), 3.66 (m, 1H), 4.7 (m, 1H), 6.51 (d, 1H, J=8.4 Hz), 6.61 (d, 1H,J=8.4 Hz).

Step 7:[1,3-cis]1,3-Bis(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranDihydrochloride

Absolute ethyl alcohol was saturated with anhydrous hydrogen chlorideand added to 212 mg (0.96 mmol) of[1,3-cis]1,3-bis(aminomethyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyranfrom Step 6. The solution was heated to reflux temperature. After 45 minat reflux temperature, a precipitate formed and the volume of thereaction mixture was reduced to 5 mL. Diethyl ether was added untilprecipitation was complete and the precipitate was collected by vacuumfiltration. The solid was washed with diethyl ether and dried in avacuum oven at 80° C. overnight to give 280 mg (96% yield) of the titlecompound as a fine white powder, m.p. >260° C.; IR 3320, 3040, 1590,1500, 1290 cm⁻¹ ; DCI MS: 225 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO) δ: 2.38 (dd,1H, J=16.5, 12 Hz), 2.76 (m, 2H), 2.97 (m, 1H), 3.52 (m, 2H), 3.9 (m,1H), 4.83 (m, 1H), 6.54 (d, 1H, 8.1 Hz), 6.7 (d, 1H, J=8.1 Hz), 8.25 (brs, 6H), 8.6 (s, 1H), 9.4 (s, 1H). Analysis calculated for C₁₁ H₁₈ Cl₂ N₂O₃ : C, 44.46; H, 6.11; N, 9.43. Found: C, 44.70; H, 6.04; N, 9.22.

EXAMPLE 155[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-hydroxymethyl-1H-2-benzopyranHydrochloride Step 1:[1,3-cis]1-Aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran

Lithium aluminum hydride (1.1 mL of 1.0M solution in diethyl ether, 1.1mmol) was added dropwise to a solution of 370 mg(1.1 mmol) of1-azidomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran,the product of Step 4 of Example 154, in 10 mL of anhydrous diethylether at 0° C. The reaction mixture was allowed to warm to ambienttemperature and stirred for 40 min. The reaction mixture was cooled to0° C. and quenched by the sequential addition of 42 μL of water, 42 μLof 15% aqueous sodium hydroxide solution and 126 μL of water. Thesolution was dried over anhydrous magnesium sulfate and filtered. Thefiltrate was concentrated in vacuo to give 263 mg (77% yield) of thetitle compound as a white powder; DCI MS: 306 (M+H)⁺ ; ¹ H NMR (CDCl₃)δ: 1.4-1.95 (m, 13H), 2.6 (m, 2H), 3.03 (dd, 1H, J=13.5, 5.7 Hz), 3.23(dd, 1H, J=13.5, 2.7 Hz), 3.7 (dd, 1H, J=11.7, 7.5 Hz), 3.77-3.9 (m,2H), 6.52 (d, 1H, J=8.4 Hz), 6.62 (d, 1H, J=8.4 Hz).

Step 2:[1,3cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-hydroxymethyl-1H-2-benzopyranHydrochloride

Absolute ethyl alcohol was saturated with anhydrous hydrogen chlorideand added to a suspension of 256 mg (0.83 mmol) of[1,3-cis]1-aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyranfrom Step 1 in 2 mL of ethanol. The reaction mixture was heated toreflux temperature. After 1.5 h at reflux temperature, a precipitate hadformed. The solvents were evaporated down under reduced pressure toapproximately 5 mL. Diethyl ether was added until the precipitation wascomplete and the solid was collected by vacuum filtration, washed withdiethyl ether and dried in a vacuum oven at 80° C. overnight to give 160mg (73% yield) of the title compound as an off-white powder, m.p. 235°C.; DCI MS: 226 (M+H)⁺ ; IR: 3200, 1590, 1500, 1295, 1050 cm⁻¹ ; ¹ H NMR(d₆ -DMSO) δ: 2.28 (dd, 1H, J=16.8, 11.4 Hz), 2.66 (dd, 1H, J=16.8, 3.0Hz), 2.83 (dd, 1H, J=12.3, 9.3 Hz), 3.45-3.7 (m, 4H), 4.8 (m, 2H), 6.51(d, 1H, J=8.4 Hz), 6.67 (d, 1H, J=8.4 Hz), 8.05 (br s, 3H), 8.48 (br s,1H), 9.3 (br s, 1H). Analysis calculated for C₁₁ H₁₆ ClNO₄ : C, 50.48;H, 6.16; N, 5.35. Found: C, 50.64; H, 6.24; N, 5.20.

EXAMPLE 156[1,3-cis]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-pyrrolidinylmethyl-1H-2-benzopyranDihydrochloride Step 1:[1R,3S]1-Azidomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-1H-2-benzopyran

Methanesulfonyl chloride (0.146 mL, 1.89 mmol) was added dropwise to asolution of 0.57 g (1.72 mmol) of[1R,3S]1-azidomethyl-5,6-cyclohexylidene-dioxy-3,4-dihydro-3-hydroxymethyl-1H-2-benzopyran,the product of Step 4 of Example 154, and 0.36 mL (2.58 mmol) oftriethylamine in 15 mL of methylene chloride at 0° C. The reactionmixture was stirred for 30 min at 0° C. then transferred to a separatoryfunnel and diluted with 45 mL of diethyl ether. The layers wereseparated and the organic layer was washed with 2×20 mL of water, 2×20mL of 1N hydrochloric acid and 20 mL of brine, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure to405 mg of white foam. The foam was dissolved in 20 mL of dimethylformamide (DMF) and an excess amount of pyrrolidine was added to thissolution. The reaction mixture was heated at 95° C. for 2.5 h thenpoured into 75 mL of water. The aqueous solution was extracted with 3×40mL of diethyl ether. The combined ether extracts were washed with 2×30mL of water and brine, dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel eluted with 10% methanol in methylenechloride to give 210 mg (55% yield) of the title compound as a whitefoam; DCI MS: 385 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.4-1.9 (m, 14H), 2.5-2.9(m, 8H), 3.45 (dd, 1H, J=13.2, 6.6 Hz), 3.68 (dd, 1H, J=13.2, 2.4 Hz),3.9 (m, 1H), 4.97 (m, 1H), 6.45 (d, 1H, J=8.1 Hz), 6.6 (d, 1H, J=8.1Hz).

Step2:[1,3-cis]1-Aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-1H-2-benzopyran

Lithium aluminum hydride (0.52 mL of a 1.0M solution, 0.52 mmol) wasadded dropwise to a solution of 20 mg (0.52 mmol) of 1,3-cis1-azidomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-1H-2-benzopyran,from Step 1, in 10 mL of anhydrous diethyl ether at 0° C. The reactionmixture was allowed to warm to ambient temperature and it was stirred atambient temperature for 40 min. The reaction mixture was then cooled to0° C. and quenched by the sequential addition of 20 μL of water, 20 μLof 15% aqueous sodium hydroxide solution and 60 μL of water. Theresultant solution was dried over anhydrous magnesium sulfate and theprecipitate filtered. Diethyl ether saturated with anhydrous hydrogenchloride was then added dropwise to the filtrate to precipitate thehydrochloride salt of[1,3-cis]1-aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-1H-2-benzopyranwhich was collected by vacuum filtration yielding 220 mg (98% yield) ofthe title compound as its hydrochloride salt, a white solid; DCI MS: 359(M+H)⁺.

Step 3:[1,3-cis]1-Aminomethyl-5,6-dihydroxy-3-pyrrolidinylmethyl-1H-2-benzopyranDihydrochloride

Absolute ethanol (10 mL) was saturated with anhydrous hydrogen chlorideand added to 187 mg (0.44 mmol) of the product of Step 2,[1,3cis]1-aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-3-pyrrolidinylmethyl-1H-2-benzopyran.The reaction mixture was heated to reflux temperature. After 2 h atreflux temperature, a precipitate formed and the reaction mixture wascooled to ambient temperature. The volume of the reaction mixture wasreduced under reduced pressure to approximately 5 mL. Diethyl ether wasadded to the concentrate to precipitate the product which was collectedby vacuum filtration and washed with diethyl ether. The solid was driedin a vacuum oven at 80° C. overnight to give 146 mg (96% yield) of thetitle compound as a fine white powder, m.p. >280° C.; IR 3400, 3200,2960, 1510, 1295 cm⁻¹ ; DCI MS: 279 (M+H)⁺ ; ¹ H NMR (D₆ -DMSO) δ: 2.0(m, 4H), 2.33 (dd, 1H, J=16.2, 10.8 Hz), 3.1 (m, 2H), 3.4 (m, 2H), 3.6(m, 3H), 4.05 (m, 1H), 4.93 (m, 1H), 6.54 (d, 1H, J=8.7 Hz), 6.7 (d, 1H,J=8.7 Hz), 8.4 (br s, 3H), 8.6 (s, 1H), 9.4 (s, 1H), 10.6 (br s, 1H).

Analysis calculated for C₁₅ H₂₄ Cl₂ N₂ O₃ : C, 51.29; H, 6.89; N, 7.97.Found: C, 50.94; H, 6.82; N, 7.76.

EXAMPLES 157-160

Following the synthesis described in Example 156, using3-(benzyloxy)propylene oxide and the appropriate alkyl or cycloalkylamine, Examples 157 and 158 were prepared as disclosed in Table 6, astheir dihydrochloride salts. Following the procedures described inExamples 154 and 155, using 4-(benzyloxy)butylene oxide, Examples 159and 160 were prepared as disclosed in Table 6. The structure of each wasconfirmed by melting point, mass spectra and elemental analysis asdesignated.

                                      TABLE 6                                     __________________________________________________________________________    Examples 157-160                                                                                                        Elemental Analysis                  Ex. No.                                                                            Compound*             Amine  mp °C.                                                                     MS**                                                                              C      H  N                         __________________________________________________________________________    157                                                                                 ##STR200##                                                                                          ##STR201##                                                                          255 295 c: 49.06 f: 49.05                                                                    6.59 6.68                                                                        7.63 7.42                 158                                                                                 ##STR202##                                                                                          ##STR203##                                                                          265 293 c: 52.61 f: 52.8                                                                     7.17 7.21                                                                        7.67 7.53                 159                                                                                 ##STR204##                  >250                                                                              239 c: 46.52 + 1/4 EtOH f:                                                               6.72 6.59                                                                        8.68 8.40                 160                                                                                 ##STR205##                  224 240 c: 51.93 +0.1 H.sub.2 O f:                                                    51.79  6.61 6.52                                                                        5.05 4.75                 __________________________________________________________________________     *all compounds 1-3 cis unless indicated otherwise                             **DCl MS (M + H)+-                                                       

EXAMPLES 161-172

Following the synthesis illustrated in Scheme V using the appropriateacylating agent Examples 161-172 were prepared as disclosed in Table 7,as their hydrochloride salts. The structure of each was confirmed bymelting point, mass spectra and elemental analysis as designated.

                                      TABLE 7                                     __________________________________________________________________________    Examples 161-169                                                              Ex.                                                Elemental Analysis         No.                                                                              Compound*                  Acyl chloride                                                                              mp °C.                                                                     MS**                                                                              C     H  N                 __________________________________________________________________________    161                                                                               ##STR206##                                                                                               ##STR207##  >260                                                                              267 c: f:  na                  162                                                                               ##STR208##                                                                                               ##STR209##  175 337 c: 57.65 + 1/2 EtOH f:                                                        58.05 8.14 7.82                                                                        7.07 6.78         163                                                                               ##STR210##                                                                                               ##STR211##  183-4                                                                             337 c: 55.30 +1 H.sub.2 O                                                         f: 55.17                                                                            7.98 7.61                                                                        7.17 7.13         164                                                                               ##STR212##                                                                                               ##STR213##  188 329 c: 55.82 +1.25 H.sub.2                                                        O f:                                                                                6.12 6.00                                                                        7.23 7.01         165                                                                               ##STR214##                                                                                               ##STR215##  165 371 c: 53.08 f:                                                                         6.93 6.86                                                                        6.88 6.70         166                                                                               ##STR216##                                                                                               ##STR217##  >250                                                                              309 c: 51.38 +0.8 HCl f:                                                          51.48 6.95 6.88                                                                        7.49 7.37         167                                                                               ##STR218##                                                                                               ##STR219##  235 408 c: 48.23 + 1/4 H.sub.2                                                        O f:                                                                                4.61 4.59                                                                        6.25 6.12         168                                                                               ##STR220##                                                                                               ##STR221##  >250                                                                              319 c: 53.49 + 1/4 H.sub.2                                                        O f:                                                                                5.47 5.52                                                                        7.80 7.59         169                                                                               ##STR222##                                                                                               ##STR223##  >250                                                                              295 c: 53.73 + 1/4 H.sub.2                                                        O f:                                                                                7.06 6.90                                                                        8.35 8.06         170                                                                               ##STR224##                                                                                               ##STR225##  >250                                                                              330 c: 48.58 +0.1 H.sub.2                                                         O f:                                                                                5.52 5.66                                                                        10.00  9.70       171                                                                               ##STR226##                                                                                               ##STR227##  >250                                                                              295 c: 54.18 +1 EtOH f:                                                           54.07 7.76 7.70                                                                        7.43 7.28         172                                                                               ##STR228##                                                                                               ##STR229##  234 281 c: 49.06 f:                                                                         6.50 6.35                                                                        7.43 7.48         __________________________________________________________________________     *all compounds 1-3 cis unless indicated otherwise;                            **DCl MS (M + H)+-                                                       

EXAMPLES 173-175

Following the synthesis described in Examples 154 and 155, using4-(benzyloxy)butylene oxide and the procedure for N-methylationdescribed in Example 111, Examples 173-175 were prepared as shown belowin Table 8, as their hydrochloride salts. The structure of each wasconfirmed by melting point, mass spectra and elemental analysis asdesignated.

                                      TABLE 8                                     __________________________________________________________________________    173-175                                                                                                           Elemental Analysis                        Ex. No.                                                                            Compound*              mp °C.                                                                     MS**                                                                              C      H  N                               __________________________________________________________________________    173                                                                                 ##STR230##            >246                                                                              253 c: 47.61 +0.4 MeOH f:                                                                7.04 6.83                                                                        8.29 7.89                       174                                                                                 ##STR231##            >243                                                                              254 c: 53.88 f: 53.62                                                                    6.96 6.99                                                                        4.83 4.90                       175                                                                                 ##STR232##            >260                                                                              253 c: 45.55 +0.3 CH.sub.2 Cl.sub.2 f:                                            45.55  6.50 6.29                                                                        7.99 8.37                       __________________________________________________________________________     *all compounds 1-3 cis unless indicated otherwise;                            **DCl MS (M + H)+-                                                       

EXAMPLE 176[1,3-cis]1-Aminomethyl-3-cyclohexyl-6,7-dihydroxy-1,3,4,5-tetrahydro-2-benzoxepinHydrochloride Step 1:Spiro[(4-methyl-1,3-benzodioxole)-2.1'-cyclohexane]

A catalytic amount of p-toluenesulfonic acid (approximately 50 mg) wasadded to a solution of 2,3-dihydroxytoluene (10 g, 80.7 mmol) andcyclohexanone (8.3 mL, 81 mmol) in 150 mL of cyclohexane. The reactionmixture was heated to reflux temperature and the water produced in thecondensation reaction was removed using a Dean Stark trap. After 6 h,the solution was concentrated to approximately 50 mL and purified on asilica gel column (10 cm×6 cm) eluted with hexane to give 14 g of thetitle compound as a colorless liquid; ¹ H NMR (CDCl₃) δ: 1.5 (m, 2H),1.7 (m, 4H), 1.9 (m, 4H), 2.2 (s, 3H), 6.6 (m, 3H).

Step 2:1-Cyclohexyl-2-(2',3'-cyclohexylidenedioxy-4'-methylphenyl)ethanol and1-Cyclohexyl-3-(2',3'-cyclohexylidenedioxyphenyl-1-propanol

N-Butyl lithium (23 mL of a 2.1M solution in hexane, 49 mmol) was addeddropwise to a solution ofspiro[(4-methyl-1,3-benzodioxole)-2,1'-cyclohexane](9 g, 44 mmol), fromStep 1, in 60 mL of THF at 0° C. The reaction mixture was allowed towarm to 25° C. and stirred at ambient temperature for 4 h. The reactionmixture was then cooled to 0° C. and 1-cyclohexylethylene oxide wasadded. The reaction mixture was stirred for 2 h at 25° C. and 30 min at50° C. then poured into 100 mL of saturated aqueous ammonium chloridesolution and extracted with 3×100 mL of diethyl ether. The combinedether extracts were washed with water and brine, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The titlecompounds were separated by column chromatography on silica gel elutedwith 5% ethyl acetate in hexane to give 5.12 g (35% yield) of1-cyclohexyl-2-(2',3'-cyclohexylidenedioxy-4'-methylphenyl)ethanol and3.63 g (25% yield) of1-cyclohexyl-3-(2',3'-cyclohexylidenedioxyphenyl)-1-propanol.

Step3:[1,3-cis]1-Bromomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2-benzoxepinHydrochloride

Boron trifluoride etherate (1.47 mL, 12 mmol) was added dropwise to asolution of 2 g (6.06 mmol) of1-cyclohexyl-3-(2',3'-cyclohexylidenedioxy-phenyl)-1-propanol from Step2 and bromoacetaldehyde dimethyl acetal (0.716 mL, 6.06 mmol) in 30 mLof methylene chloride at -20° C. The temperature of the reaction mixturewas maintained between -10° C. and -5° C. for 1 h. The reaction mixturewas then diluted with 100 mL of diethyl ether and washed with 2×50 mL ofaqueous sodium carbonate solution and 50 mL of brine. The organicsolution was dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel eluted with 2% ethyl acetate in hexane to give 1.2 g (46%yield) of the title compound as a colorless foam.

Step 4:[1,3-cis]1-Aminomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2-benzoxepinHydrochloride

Lithium azide (590 mg, 12 mmol) was added to a solution of 1.05 g (2.4mmol) of[1,3-cis]1-bromomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2-benzoxepanehydrochloride, from Step 3, in 10 mL of DMF at 25° C. The reactionmixture was heated to 65° C., stirred at 65° C. for 2.5 h, cooled toambient temperature and poured into 100 mL of water. The aqueoussolution was extracted with 3×50 mL of diethyl ether. The combined etherextracts were washed with 75 mL of water and 75 mL of brine, dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluted with2% ethyl acetate in hexane to give 850 mg (89% yield) of[1,3-cis]-1-azidomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2-benzoxepinhydrochloride. This azide intermediate was dissolved in 25 mL of diethylether and lithium aluminum hydride (2.1 mL of a 1M solution in diethylether) was added to the solution at 0° C. After warming the reactionmixture to ambient temperature and stirring for 1 h, the reactionmixture was cooled to 0° C. and the reaction quenched by the sequentialaddition of 80 μL of water, 80 μL of 15% aqueous sodium hydroxidesolution and 240 μL of water. The precipitate was filtered and washedwith diethyl ether. The filtrate was concentrated and the residueredissolved in diethyl ether. The ether solution was treated withdiethyl ether saturated with anhydrous hydrogen chloride. Theprecipitate was collected by vacuum filtration and dried to give 770 mg(90% yield) of the title compound as a colorless solid, m.p. 250° C.;DCI MS: 372 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 0.9-1.9 (m, 23H), 2.7 (m, 1H),3.02 (m, 1H), 3.3 (t, 1H, J=11.4 Hz), 3.52 (m, 2H), 4.97 (dd, 1H,J=11.4, 2.9 Hz), 6.45 (d, 1H, J=7.5 Hz), 6.5 (d, 1H, J=7.5 Hz), 8.5 (brs, 2H).

Step 5:[1,3-cis]1-Aminomethyl-3-cyclohexyl-6,7-dihydroxy-1,3,4,5-tetrahydro-2-benzoxepinHydrochloride

[1,3-cis]1-Aminomethyl-3-cyclohexyl-6,7-cyclohexylidenedioxy-1,3,4,5-tetrahydro-2-benzoxepinhydrochloride (200 mg, 0.49 mmol), from Step 4, was added to a 1Nsolution of anhydrous hydrogen chloride in ethyl alcohol. The reactionmixture was heated to 50° C. and monitored by TLC analysis. After twohours the solution was concentrated to approximately 1 mL and theresidue triturated with diethyl ether. The solid was collected by vacuumfiltration, washed with diethyl ether and dried to give 62 mg (40%yield) of the title compound as a colorless powder, m.p. 216°-219° C.;DCI MS: 292. (M+H)⁺. Analysis calculated for C₁₇ H₂₆ ClNO₃ : C, 62.28;H, 7.99; N, 4.27. Found: C, 62.22; H, 8.05; N, 4.14.

EXAMPLE 177[1,3-cis]1-Aminomethyl-3-cyclohexyl-3,4-dihydro-5,6-dihydroxy-7-methyl-1H-2-benzopyranHydrochloride

1-Cyclohexyl-2-(2',3'-cyclohexylidenedioxy-4'-methylphenyl)ethanol, fromStep 2 of Example 176, was converted to the title compound by theprocedures described in Example 176 above, Steps 3-5, m.p. 168°-170° C.;DCI MS: 292 (M+H)⁺. Analysis calculated for C₁₇ H₂₆ ClNO₃ +1/2H₂ O: C,60.61; H, 8.077; N, 4.16. Found: C, 60.39; H, 7.92; N, 4.12.

EXAMPLE 178 [1S,3R]1-Aminomethyl-3-phenyl-5,6-dihydroxy-1H-2-benzopyranHydrochloride Step 1:2-(2',3'-Cyclohexylidenedioxyphenyl)-1-phenylethanone

A solution of 15.5 g (50 mmol) of2-(2',3'-cyclohexylidenedioxyphenyl)-1-phenylethanol prepared fromstyrene oxide (commercially available from Aldrich Chemical Company) bythe procedure described in Step 2 of Example 47, in 60 mL of methylenechloride was added dropwise to a mixture of 60 g (28 mmol) of pyridiniumchlorochromate (PCC) and 35 g of Celite® filter aid in 300 mL ofmethylene chloride at ambient temperature. After 4 h, the reactionmixture was diluted with 200 mL of diethyl ether and filtered throughsilica gel. The chromium-containing residue was washed several timeswith diethyl ether. The filtrate was concentrated under reduced pressureto give 14 g (90% yield) of the title compound as a yellow syrup; DCIMS: 326 (M+NH₄)⁺, 309 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 1.4-1.9 (m, 10H), 4.2(s, 2H), 6.7 (m, 3H), 7.42 (m, 2H), 7.53 (m, 1H), 8.05 (m, 2H).

Step 2: [1R]2-(2',3'-cyclohexylidenedioxyphenyl)-1-phenylethanol

A solution of 754 mg (2.45 mmol) of2-(2',3'-cyclohexylidenedioxyphenyl)-1-phenylethanone, from Step 1, in 1mL of THF was added to a solution of 936 mg (2.9 mmol) of (-)B-chlorodiisopinocampheylborane (commercially available from AldrichChemical Company) in 3 mL of THF at -20° C. After storing the resultantsolution for 12 h at -15° C., the solvent was evaporated, the residuewas dissolved in 15 mL of diethyl ether and 565 mg of diethanolamine wasadded. The mixture was stirred for 30 min. The precipitate was removedby filtration through Celite® filter aid. The filtrate was concentratedand the residue purified by column chromatography on silica gel elutedwith methylene chloride/hexane/diethyl ether (100:20:1) to give 546 mg(72% yield) of the title compound; DCI MS: 328 (M+NH₄)⁺ ; ¹ H NMR(CDCl₃) δ: 1.4-1.9 (m, 10H), 2.3 (br s, 1H), 3.0 (m, 2H), 4.98 (dd, 1H,J=7.5, 5.0 Hz), 6.62 (m, 3H), 7.3 (m, 5H).

Step 3:[1S,3R]1-Aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl-1H-2-benzopyranHydrochloride

[1R]2-(2',3'-Cyclohexylidenedioxyphenyl)-3-phenylethanol was convertedto[1S,3R]1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl-1H-2-benzopyranby the procedures detailed in Step 3 of Example 47 and Steps 1-3 ofExample 48, m.p. 158°-160° C.; [alpha]_(D) =110° (c 0.52, 1N HCl); DCIMS: 272 (M+H)⁺. Analysis calculated for C₁₆ H₁₈ ClNO₃ : C, 60.60; H,6.05; N, 4.42. Found: C, 60.71; H, 6.2; N, 4.31.

EXAMPLE 179[1R,3S]3-Adamantyl-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranHydrochloride Step 1:1-Aza-2-boro-3-oxa-1,4,4-triphenyl-bicyclo[3.3.0]octane

Diphenyl-(2R-2'-pyrrolidinyl)methanol (610 mg, 2.41 mmol) andphenylboronic acid (294 mg, 2.41 mmol) were taken up in 25 mL oftoluene. The diphenyl-(2R-2'-pyrrolidinyl)methanol was prepared asdescribed by E. J. Corey et al. in J American Chem Soc. 109:5551-53(1987). The reaction mixture was heated at reflux temperature for 4 hunder a nitrogen atmosphere using a Dean Stark trap filled with 4 Åmolecular sieves to remove water. The reaction was then cooled andconcentrated in vacuo to afford the title compound as a colorless oil.The product was carried on to the next step without purification.

Step 2: [1R]1-(1'-adamantyl)-2-bromo-1-hydroxyethane

Diborane in THF (5.2 mL of 1.0M THF solution, 5.2 mmol) was addeddropwise over a period of 10 min to a solution of 2.22 g (8.63 mmol) of1-adamantyl-bromomethyl ketone (commercially available from AldrichChemical Co.) and 2.1 mL of a 0.2M solution in THF (0.43 mmol) of1-aza-2-boro-3-oxa-1,4,4-triphenyl-bicyclo[3.3.0]octane, from Step 1, in16 mL of anhydrous THF. The reaction mixture was stirred for 10 min atambient temperature and then cooled to ˜0° C. in an ice bath and thenthe reaction was quenched by the careful addition of 3 mL of methanol.Diethyl ether saturated with hydrogen chloride (2 mL) was added and thesolution was allowed to warm to ambient temperature. The solution wasstirred at ambient temperature for 0.5 h and then it was poured into 100mL of diethyl ether and 100 mL of water. The organic layer was washedwith 1N aqueous hydrochloric acid solution, aqueous saturated sodiumbicarbonate and brine, dried over anhydrous magnesium sulfate, filteredand concentrated under reduced pressure to give 216 mg (96% yield) ofthe title compound as a white solid.

Step. 3: [1R]1-(1'-adamantyl)-ethylene Oxide

A 15% aqueous solution of sodium hydroxide was added to a solution of1.9 g (7.34 mmol) of [1R]1-(1'-adamantyl)-2-bromo-1-hydroxyethane, fromStep 2, in 50 mL of diethyl ether The mixture was stirred vigorously atambient temperature for ˜18 h. The mixture was then diluted with 100 mLof diethyl ether and 50 mL of water. The aqueous layer was extractedwith 50 mL of diethyl ether. The combined organic layers were washedwith 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to afford 1.3g of the title compound. The product was carried on to the next stepwithout purification.

Step 4:[1S]1-(1'-Adamantyl-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol

n-Butyl lithium (6.7 mL of a 1.48M solution in hexane, 9.9 mmol) wasadded over a 10 min period to a solution ofspiro[(1,3-benzodioxole)-2,1'-cyclohexane] in 14 mL of THF at 0° C. Thereaction mixture was allowed to warm to ambient temperature over a 0.5 hperiod and then it was stirred for 3.5 h at ambient temperature. Thereaction mixture was cooled to -78° C. and a solution of 1.2 g (6.74mmol) of [1R]1-(1'-adamantyl)-ethylene oxide, from Step 3, in 5 mL ofTHF was added. Boron trifluoride etherate (1.15 mL, 9.44 mmol) was thenadded dropwise over a 7 min period. After 30 minutes, 25 mL of aqueoussaturated sodium bicarbonate solution was added, followed by 25 mL ofethyl acetate. The reaction mixture was allowed to warm to ambienttemperature and transferred to a separatory funnel. Ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate solution (25 mL) were addedto the funnel and the layers were separated. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith 2×50 mL of aqueous sodium bicarbonate solution and brine, driedover anhydrous magnesium sulfate and concentrated under reduced pressureto an oil. The crude product was dissolved in 20 mL of methanol and thesolution was cooled to 0° C. The precipitate was collected by filtrationand washed with cold methanol to give 2.21 g (89% yield) of the desiredproduct. The title compound was recrystallized from methanol to give 1.6g of the title compound, m.p. 72°-73° C.; [alpha]_(D) =-27.75° (c 1.63,CHCl₃); DCI MS: 386 (M+NH₄)⁺. ¹ H NMR (CDCl₃) δ: 0.9 (q, 0.25 H, J=6 Hz,MeOH solvate), 1.5-2.1 (m, 25H), 2.5 (dd, 1H, J=13.5, 10.5 Hz), 2.87(dd, 1H, J=13.5, 2.0 Hz), 3.3 (m, 1H), 3.5 (d, 0.75H, J=6 Hz, MeOHsolvate). Analysis calculated for C₂₄ H₃₂ O₃ +0.25MeOH: C, 77.35; H,8.83. Found: C, 77.09; H, 8.77.

Step 5:[1R,3S]3-(1'-Adamantyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran

Trimethylsilyltriflate (73 μL, 0.38 mmol) was added to a mixture of 3.5g (9.5 mmol) of[1S]1-(1'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol,from Step 4, and N-formylacetaldehyde dimethyl acetal (2 g, 15.2 mmol)in 20 mL of acetonitrile. The reaction mixture was heated at a gentlereflux for 2 h and an additional 50 μL (0.26 mmol) oftrimethylsilyltriflate was added. A precipitate formed and after 4 h thereaction mixture was cooled to 0° C. The precipitate was collected byfiltration, washed with cold acetonitrile and dried to afford 2.92 g(70% yield) of the title compound as colorless crystals, m.p. 220°-221°C.; [alpha]_(D) =-33.15° (c 1.63, CHCl₃); DCI MS: 438 (M+H)⁺. ¹ H NMR(d₆ -DMSO) δ: @140° C. 1.5-2.05 (m, 25H), 2.5 (m, 2H), 2.8 (m, 1H), 3.1(dd, 1H, J=7.5, 3.0 Hz), 3.32 (m, 1H) 3.71 (br s, 1H), 4.65 (br s, 1H),6.6 (m, 2H), 8.05 (br s, 1H).

Step 6:[1R,3S]3-(1'-Adamantyl)-1-aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran

[1R,3S]3-(1'-Adamantyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran(2.8 g, 6.41 mmol) was mixed together with 20 mL of 15% aqueous sodiumhydroxide solution, 30 mL of methanol and 20 mL of THF. The mixture washeated at ˜50° C. for 3 h and then it was concentrated in vacuo to ˜30mL. The concentrated mixture was diluted with 150 mL of ethylacetate/methylene chloride (2:1) and 50 mL of water. The organic layerwas washed with 2×50 mL of water and 50 mL of brine. The combinedaqueous layers were extracted with ethyl acetate/methylene chloride(2:1) and discarded. The combined organic layers were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to give2.64 g of the title compound as a light tan colored foam. The productwas carried on to the next step without purification.

Step 7:[1R,3S]3-(1-Adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranHydrochloride

A solution of hydrochloric acid in 10:1 THF/water (20 mL of a 4Nsolution) was added to[1R,3S]3-(1'-adamantyl)-1-aminomethyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1H-2-benzopyran(1.1 g, 2.7 mmol) from Step 6, and the reaction mixture was heated atreflux temperature for 3 h. The reaction mixture was cooled to 0° C. and10 mL of diethyl ether was added. At the onset of crystallization anadditional 10 mL of diethyl ether was added. After 30 min theprecipitate was removed by filtration, washed with diethyl ether anddried to give 0.81 g (82% yield) of the title compound as a colorlesssolid; DCI MS: 330 (M+H)⁺. ¹ H NMR (CD₃ OD) δ: 1.65-2.05 (m, 15H), 2.6(dd, 1H, J=16.5, 12.0 Hz), 2.72 (dd, 1H, J=16.5, 3.0 Hz), 3.08 (dd, 1H,J=12.6, 7.5 Hz), 3.15 (dd, 1H, J=12.0, 3.0) 3.54 (dd, 1H, J=12.6, 3.2Hz), 4.85 (m, 1H), 6.5 (d, 1H, J=8.4 Hz), 6.69 (d, 1H, J=8.4 Hz).

EXAMPLE 180[1,3-cis]5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl-1,2,3,4-tetrahydronaphthaleneHydrobromide Step 1:1-Cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene

To a suspension of 10 g (35 mmol) of5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the productof Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide(commercially available from Aldrich Chemical Company) and approximately50 mg of anhydrous aluminum chloride (AlCl₃). The reaction mixture washeated at 60° C. for 3 h then cooled to ambient temperature and dilutedwith 150 mL of toluene. The volume of the reaction mixture was reducedin vacuo to approximately 50 mL. The resultant trimethylsilyl adduct wasdehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg ofp-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1h. The reaction mixture was cooled to ambient temperature, the layersseparated and the organic layer washed with water, aqueous sodiumbicarbonate solution and brine, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure to a colorless oil. Theoil was purified by column chromatography on silica gel eluted with 20%ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound,m.p. 109°-110° C.

Step 2: 1-Cyano-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene

Sodium borohydride (6.8 g) was added to a suspension of 6.8 g (23.3mmol) of 1-cyano-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, fromStep 1, in 100 mL of absolute ethanol and the reaction mixture washeated at reflux temperature for 1.5 h. The solvent was evaporated underreduced pressure and the residue was dissolved in ethyl acetate. Theethyl acetate solution was washed with 1N aqueous hydrochloric acidsolution, aqueous sodium bicarbonate solution and brine, dried overanhydrous magnesium sulfate, filtered and concentrated to an oil. Theoil was triturated with heptane to give 5.63 g (82% yield) of the titlecompound as a white crystalline solid, m.p. 118°-121° C.

Step 3:5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic Acid

A mixture of 5.6 g (19.1 mmol) of1-cyano-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene, from Step2, 40 mL of 5% aqueous potassium hydroxide solution and 90 mL ofethylene glycol was heated at reflux temperature for 8 h. The reactionmixture was then cooled to -20° C. and made acidic by the addition ofcold concentrated aqueous hydrochloric acid solution. The acidicsolution was extracted with methylene chloride and the organic extractswere washed with brine, dried over anhydrous magnesium sulfate, filteredand evaporated to give 5 g (84% yield) of the title compound which wasused in the next step without purification.

Step 4:N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydro-naphthalene-1-carboxamide

5,6-Dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid(5 g, 16 mmol), from Step 3, was suspended in 100 mL of toluene and 5 mLof oxalyl chloride was added. The reaction mixture was heated at refluxtemperature for 1.5 h under a nitrogen atmosphere. The solvent wasevaporated and excess reagents removed from the residue as an azeotropewith toluene (2×40 mL). The acid chloride and 2 g (20 mmol) ofN,O-dimethylhydroxylamine hydrochloride was dissolved in 80 mL ofethanol-free chloroform. The solution was cooled to 0° C. and 3.3 mL ofpyridine was added slowly. The reaction mixture was allowed to warm toambient temperature and stirred at ambient temperature for approximately4 h then evaporated to dryness. The residue was dissolved in a 1:1mixture of diethyl ether and methylene chloride and washed with brine.The layers were separated and the organic layer dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure togive the title compound as an oil in 98% yield. The product of Step 4was used in the next step without purification.

Step 5:5,6-Dimethoxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthaleneHydrochloride

N-Methoxy-N-methyl-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaph-thalene-1-carboxamide(3.3 g), from Step 4, was dissolved in 80 mL of dry THF and the solutionwas cooled to 0° C. An excess (3-4 equivalents) of2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane-1-propyl magnesiumbromide was added and stirred overnight. The2,2,5,5-tetramethyl-1-aza-2,5-disilacyclo-pentane-1-propyl magnesiumbromide was prepared as described by Basha and DeBernardis inTetrahedron Letters, 25, 5271-5274 (1984). The reaction mixture wascooled to 0° C., 10% hydrochloric acid solution in ethanol was addedslowly, and it was allowed to warm to ambient temperature again. Thereaction mixture was stirred at ambient temperature for 3 h and thesolvent was evaporated. The residue was dissolved in 50 mL of methanol,cooled to 0° C. and treated with an excess of sodium cyanoborohydride.The reaction mixture was allowed to warm to ambient temperature andstirred at ambient temperature for 2 h. The solvent was removed in vacuoand the residue was redissolved in diethyl ether and washed with water.The layers were separated and the acidic aqueous layer was made basicand extracted with methylene chloride. The methylene chloride extractwas dried over anhydrous magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica geleluted with ethyl acetate/formic acid/water (18:1:1) to give a totalyield, after concentration in vacuo, of 2.42 g (42% yield) of the titlecompound as individual diastereomers as their formate salts. Eachdiastereomer was converted to its hydrochloride salt as follows: theformate salt was dissolved in water and the aqueous solution was madebasic with sodium hydroxide. The free base was extracted with methylenechloride and the organic layer was washed with brine, dried overanhydrous magnesium sulfate, filtered and concentrated under reducedpressure. The residue was dissolved in diethyl ether and a saturatedsolution of hydrogen chloride gas in methanol was added to precipitatethe hydrochloride salt. The first compound to elute from the column gave274 mg (7% yield) of the [1R,3S,2'R] isomer, m.p. 105°-106° C. Thestructure was confirmed by NMR and X-ray crystallographic analysis(after recrystallization from acetone by slow evaporation).

The final product to elute from the column gave 400 mg(11% yield) of the[1R,3R, 2'R]isomer, m.p. 150°-152° C. The structure was confirmed by NMRand X-ray crystallographic analysis after recrystallization from acetoneby slow evaporation.

Step 6:[1,3-cis]5,6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthaleneHydrobromide

5,6-Dimethoxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalenehydrochloride (200 mg, m.p. 105°-106° C.), from Step 5, was dissolved in10 mL of methylene chloride and the solution was cooled to -78° C. undera nitrogen atmosphere. Boron tribromide (0.25 mL of a 1M solution inmethylene chloride) was added and the reaction mixture was stirred for 3h at -78° C. The reaction mixture was then allowed to warm to -20° C.for 1 h, cooled to -78° C. and quenched with 10 mL of methanol. Thesolution was evaporated to dryness and distilled with methanol threetimes to azeotrope methyl borate from the residue. The solid residue wascrystallized from methanol/ethyl acetate to give 130 mg (67% yield) ofthe title compound, m.p. 265° C. (with decomposition). Analysiscalculated for C₂₀ H₂₄ BrNO₂ +1/2H₂ O: C, 60.16; H, 6.31; N, 3.51.Found: C, 60.06; H, 6.17; N, 3.42.

EXAMPLE 181[1,3-cis]5.6-Dihydroxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaph-thaleneHydrobromide

According to the procedures described in Step 6 of Example 180,[1R,3R]5,6-dimethoxy-3-phenyl-1-(2'-pyrrolidinyl)-1,2,3,4-tetrahydronaphthalenehydrochloride (350 mg), from Step 5 of Example 180, in 10 mL ofmethylene chloride at -78° C., was treated with 472 μL of a 1M solutionof boron tribromide in methylene chloride. The title compound wasobtained (213 mg) in 61% yield after crystallization from methanol/ethylacetate, m.p. 250° C. (with decomposition). Analysis calculated for C₂₀H₂₄ BrNO₂ +1/2H₂ O: C, 60.16; H, 6.31; N, 3.51. Found: C, 60.23; H,6.24; N, 3.38.

EXAMPLE 182[1R*,8S*,9aR*]1-Amino-5,6-dihydroxy-8-phenyl-2,3,7,8,9,9a-hexahydro-phenaleneHydrobromide Step 1: 1-(3'-(3'-CarbomethoxypropanoicAcid)-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene

To a suspension of 4.0 g. (14.2 mmol) of5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the productof Example 1, in 5 mL of t-butyl alcohol was added dropwise a mixture of13 mL (99.4 mmol) of dimethyl succinate, 9.6 g (86 mmol) of potassiumt-butoxide, and 65 mL of t-butyl alcohol. After 10 mL of the mixture wasadded, the reaction was heated to 55° C. and maintained at thistemperature for the duration of the reaction. When the addition wascomplete, the reaction was heated for an addition 60 minutes and thencooled and poured into 50 mL of ice cold 2N aqueous hydrochloric acidsolution. The aqueous phase was extracted with 5×100 mL of diethylether. The combined organic layers were extracted with 5×100 mL ofaqueous saturated sodium bicarbonate solution. The combined aqueouslayers were acidified to pH 3 with 6N aqueous hydrochloric acid solutionand the product was extracted with 2×200 mL of 1:1 diethyl ether/ethylacetate. The organic phase was dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. The title compound (5.0 g, 86%yield) was obtained as an oil; MS DCI: 397 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ:2.6-2.8 (m, 4H), 3.1-3.3 (m, 1H), 3.69 (s, 3H), 3.71 (s, 3H), 3.87 (s,3H), 4.1-4.25 (m, 1H), 5.9-6.0 (m, 1H), 6.7-6.8 (m, 1H), 7.0-7.5 (m,6H).

Step 2: 1-(3'-(3'-CarbomethoxypropanoicAcid)-5,6-dimethoxy,3-phenyl-1,2,3,4-tetrahydronaphthalene

To a solution of 15.8 g (39.9 mmol) of 1-(3'-(3'-carbomethoxypropanoicacid)-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene, from step 1, in 200mL of ethyl acetate was added 3.16 g. of 10% palladium supported oncarbon. The reaction mixture was shaken under 4 atmospheres of hydrogenuntil hydrogen uptake ceased. The reaction mixture was filtered andconcentrated under reduced pressure to give 12.2 g (74% yield) of thetitle compound as an oil. The product was carried on without furtherpurification to the next step.

Step 3:1-Carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene

1-(3'-(3'-Carbomethoxypropanoicacid)-5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalene (3.5 g, 8.5mmol), from Step 2, was added to 11 g of polyphosphoric acid at 0° C.The ice bath was removed and the mixture was stirred at ambienttemperature for 3 hours. The aqueous solution was extracted with 3×50 mLof 1:1 ethyl acetate/diethyl ether. The combined organic layers werewashed with 50 mL of saturated aqueous sodium bicarbonate solution,dried over anhydrous magnesium sulfate, filtered and concentrated underreduced pressure. The product was purified by chromatography on silicagel, eluted with 20% ethyl acetate in hexanes. Four diastereomericproducts were obtained of which two were characterized.

The first diastereomer,[1R*,8S*,9aR*]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene(182-3A), was obtained in 18% yield (0.59 g) as a solid, m.p 170°-172°C.; DCI MS: 381 (M+H)⁺, 398 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ: 1.6-1.7 (m,1H), 2.1-2.2 (m, 1H), 2.6-2.7 (m, 1H), 2.9-3.1 (m, 4H), 3.2-3.4 (m, 2H),3.71 (m, 3H), 3.87 (s, 3H), 3.91 (s, 3H), 7.2-7.4 (m, 5H), 7.53 (s, 1H).

The second diastereomer,[1S*,8S*,9aR*]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene(182-3B) was obtained in 18% yield (0.60 g) as a solid, m.p 160°-161°C.; DCI MS: 381 (M+H)⁺, 398 (M+NH₄)⁺ ; ¹ H NMR (CDCl₃) δ: 2.0-2.1 (m,1H), 2.15-2.25 (m, 1H), 2.6-2.8 (m, 2H), 3.0-3.1 (m, 2H), 3.2-3.3 (m,2H), 3.4-3.5 (m, 1H), 3.7 (s, 3H), 3.83 (s, 3H), 3.91 (s, 3H), 7.2-7.4(m, 5H), 7.54 (s, 1H).

Step 4:[1R*,8S*,9aR*]1-Carbomethoxy-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene

To a solution of 0.5 g (1.3 mmol) of[1R,8S,9aR]-1-carbomethoxy-5,6-dimethoxy-3-hydroxy-8-phenyl-7,8,9,9a-tetrahydrophenalene(182-3A) in 50 mL of methanol, 50 mL of ethyl acetate, and 0.1 mL ofconcentrated aqueous hydrochloric acid was solution was added 0.2 g of5% palladium supported on carbon and the mixture was shaken under 4atmospheres of hydrogen until the gas uptake had ceased. The palladiumcatalyst was removed by filtration through Celite® filter aid and thefiltrate concentrated to give a white solid, which was carried on to thenext step without purification.

Step 5:[1R*,8S*,9aR*]5,6-Dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene-1-carboxylicAcid

Crude[1R*,8S*,9aR*]1-Carbomethoxy-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene(0.8 g., 2.1 mmol), from Step 4, was dissolved in 100 mL of methanol and8 mL of 1N aqueous sodium hydroxide solution was added. After stirringfor 3 days at ambient temperature, the methanol was removed underreduced pressure. The residue was partitioned between 50 mL of diethylether and 75 mL of water. The aqueous phase was acidified to pH 2 with6M aqueous hydrochloric acid solution and extracted with 3×25 mL of 1:1ethyl acetate/diethyl ether. The combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give 0.74 g (100% yield) of the title compoundas an oil; DCI MS: 253 (M+H)⁺. ¹ H NMR (CDCl₃) δ: 2.0-2.3 (m, 2H),2.65-2.85 (m, 2H), 2.9-3.1 (m, 6H), 3.2-3.3 (m, 1H), 3.73 (s, 3H), 3.83(s, 3H), 6.56 (s, 1H), 7.2-7.4 (m, 5H).

Step 6:[1R*,8S*,9aR*]1-Carbobenzyloxyamino-5,6:dimethoxy-8,phenyl-2,3,7,8,9,9a-hexahydrophenalene

[1R*,8S*,9aR*]5,6-Dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene-1-carboxylicacid (0.8 g, 2.3 mmol), from Step 5, and triethylamine (0.32 mL, 2.3mmol) were dissolved in 16 mL of toluene and 0.55 mL (2.5 mmol) ofdiphenylphosphoryl azide was added. The reaction mixture was heated at80° C. for 2.5 h then 0.5 mL (4.8 mmol) of benzyl alcohol was added andheating was continued at 80° C. for an additional 3 h and at 65° C. for15 h. The reaction mixture was cooled and concentrated under reducedpressure. The residue was dissolved in 25 mL of diethyl ether and theether solution was washed with 10 mL of 1N aqueous sodium hydroxidesolution and brine, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo. The product was purified by chromatography onsilica gel eluted with 20% ethyl acetate in hexanes to give 0.4 g (39%yield) of the title compound as a white solid; DCI MS: 475 (M+NH₄)⁺, 458(M+H)⁺, 367 (M-benzyl+H)⁺, 324 (M-benzyloxy-carbonyl+2H)⁺. ¹ H NMR(CDCl₃) δ: 1.6-1.7 (m, 3H), 2.2-2.35 (m, 2H), 2.6-2.75 (m, 2H), 2.9-3.0(m, 3H), 3.2-3.3 (m, 1H), 3.73 (s, 3H), 3.82 (s, 3H), 4.65-4.7 (m, 1H),5.08 (s, 2H), 6.54 (s, 1H), 7.2-7.4 (m, 10H).

Step 7:[1R*,8S*,9aR*]1-Amino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene

A suspension of 0.65 g (1.4 mmol) of[1R*,8S*,9aR*]1-carbobenzyloxy-amino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalene,from Step 6, in 50 mL of methanol and 0.1 g of 10% palladium supportedon carbon was stirred under 1 atmosphere of hydrogen for 1 hour. Thesolid dissolved as the reaction proceeded. The catalyst was removed byfiltration and the solution was concentrated under reduced pressure togive 0.4 g (87% yield) of crude title compound which was carried on tothe next step without further purification.

Step 8:[1R*,8S*,9aR*]1-Amino-5,6-dihydroxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenaleneHydrobromide

To a solution of 0.4 g (1.2 mmol) of[1R*,8S*,9aR*]1-amino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalenein 9 mL of methylene chloride at -78° C., was added dropwise 4.4 mL (4.4mmol) of a 1M solution of boron tribromide in methylene chloride. Thereaction mixture was warmed to ambient temperature for 1 hour and cooledto -78° C. and the reaction was quenched by the addition of 5 mL ofmethanol. The reaction was allowed to lo warm to ambient temperature andstirred for 1 hour. The solvent was removed in vacuo. Methanol (5 mL)was added and the solution was concentrated to remove methyl borate byazeotropic distillation. The title compound was obtained (0.32 g, 69%yield) after recrystallization from ethanol/diethyl ether as a whitesolid; DCI MS: 279 (M+H)⁺, 296 (M-NH₄)⁺. ¹ H NMR (d₆ -DMSO) δ: 1.4-1.6(m, 1H), 1.7-1.9 (m, 1H), 2.1-2.2 (m, 1H), 2.2-2.3 (m, 1H), 2.4-2.5 (m,2H), 2.7-3.2 (m, 5H), 6.41 (s, 1H), 7.2-7.4 (m, 5H), 8.0 (br s, 5H).Analysis calculated for C₁₉ H₂₂ BrNO₂ +0.5 H₂ O: C, 59.23; H, 5.99; N,3.64. Found: C, 59.26; H, 5.86; N, 3.59.

EXAMPLE 183[1S*,8S*,9aR*]1-Amino-5,6-dihydroxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenaleneHydrobromide

[1S*,8S*,9aR*]1-Amino-5,6-dimethoxy-8-phenyl-2,3,7,8,9,9a-hexahydrophenalenehydrobromide was prepared from the second isomeric product of Step 3 ofExample 182 (3B) according to the procedures described in Steps 4through 8 of Example 182; DCI MS 279 (M+H)⁺, 296 (M-NH₄)⁺. ¹ H NMR (d₆-DMSO) δ: 1.6-1.75 (m, 1H), 1.8-2.05 (m, 2H), 2.25-2.7 (m, 5H),2.85-3.05 (m, 3H), 6.37 (s, 1H), 7.1-7.4 (m, 5H), 7.7 (br s, 5H).Analysis calculated for C₁₉ H₂₂ BrNO₂ +1H₂ O: C, 57.88; H, 6.14; N,3.55. Found: C, 57.82; H, 5.74; N, 3.56.

EXAMPLE 1846,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole FormicAcid Salt Step 1:5,6-Dimethoxy-3-phenyl-2-thiophenyl-1,2,3,4-tetrahydronaphthalen-1-one

To a solution of 28.9 g (0.102 mol) of5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the productof Example 1, in 240 mL of THF was added 40.4 g (0.107 mol) ofphenyltrimethylammonium tribromide. After stirring at ambienttemperature for 1 h, 960 mL of water was added. The solution wasextracted with 3×250 mL of ethyl acetate. The combined organic phase waswashed with 3×250 mL of water, 250 mL of saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure to give an oil which was carried onwithout further purification or characterization.

A solution of sodium methoxide was prepared by the addition of 3.28 g(0.143 mol) of sodium metal to 97 mL of methanol with cooling to 0° C.Thiophenol (14.6 mL, 0.143 mol) was added dropwise over 10 minutes andthen stirred an additional 10 minutes at 0° C. A solution of the abovecrude oil in 60 mL of THF was added dropwise over 30 minutes and thereaction was then allowed to warm to ambient temperature for 4 h. Thesolvents were removed in vacuo and the residue was dissolved in amixture of 250 mL each of methylene chloride and water. The organicphase was collected and washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The product was recrystallized from ethylacetate/hexanes to give 33.15 g (83% yield from the ketone) of5,6-dimethoxy-3-phenyl-2-thiophenyl-1,2,3,4-tetrahydro-naphthalen-1-oneas a white solid; MS DCI: 391 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 3.35 (dd, 1H,J=6,18 Hz), 3.55 (dd, 1H, J=6,18 Hz), 3.71 (q, 1H, J=6 Hz), 3.82 (s,3H), 3.93 (s, 3H), 4.19 (d, 1H, J=6 Hz), 6.91 (d, 1H, J=9 Hz), 7.1-7.3(m, 8H), 7.4-7.5 (m, 2H), 7.37 (d, 1H, J=9 Hz).

Step 2: -5,6-Dimethoxy-3-phenyl-2-sulfoxophenyl-3,4-dihydronaphthalene

A solution of 20.96 g (53.7 mmol) of5,6-dimethoxy-3-phenyl-2-thiophenyl-1,2,3,4-tetrahydronaphthalen-1-onein 320 mL of ethanol was treated with 20.03 g. (0.529 mol) of sodiumborohydride. The reaction was heated to reflux temperature for 2 h, thencooled and 500 mL of water was added. The solvents were removed in vacuoand the residue was taken up in 500 mL of 1:1 diethyl ether/methylenechloride and 500 mL of water. The organic layer was removed and washedwith 100 mL each of water and brine, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The crude resultantalcohol was dehydrated by the addition of 700 mL of toluene and 3.6 g(18.9 mmol) of p-toluenesulfonic acid monohydrate and heating to refluxwith azeotropic removal of water for 30 minutes. After cooling, thesolution was washed with 3×100 mL of saturated aqueous sodiumbicarbonate, 100 mL of water, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The crude thio-enolether was carriedon directly by first, dissolution in 360 mL of methylene chloride. Thissolution was cooled to -15° C. and a solution of 12.1 g of3-chloroperoxybenzoic acid (mCPBA) in 160 mL of methylene chloride wasadded dropwise over 30 minutes. After the addition was complete, thereaction was quenched by the addition of 100 mL of aqueous saturatedsodium thiosulfate. The organic layer was separated, and washed with3×100 mL of saturated aqueous sodium bicarbonate, 100 mL of water, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure. The product was chromatographed on silica gel eluted with 25%ethyl acetate in hexanes to give 18.65 (89% yield) of5,6-dimethoxy-3-phenyl-2-sulfoxophenyl-3,4-dihydronaphthalene as a whitesolid as a mixture of diastereomers; MS DCI: 391 (M+H)⁺ ; ¹ H NMR(CDCl₃) δ: 2.9-3.1 (m, 1H), 3.1-3.3 (m, 1H), 3.46 and 3.51 (2×s, 3Htotal), 3.55 and 3.7 (2×m, 1H total), 3.83 and 386 (2×s,3H total),6.75-7.15 (m, 7H), 7.3-7.6 (m, 6H).

Step 3: N-Trimethylsilylmethyl Benzylamine

A mixture of 264 mL (2.42 mol) of benzylamine and 97.7 g. (0.796 mol) ofchloromethyltrimethylsilane was heated to 200° C. for 2.5 h then cooledto 10° C. A 0.1M sodium hydroxide solution (400 mL) was added and theproduct was extracted with 3×200 mL of diethyl ether. The combinedorganic phase was washed with 100 mL of water, dried over anhydrousmagnesium sulfate, filtered and concentrated under reduced pressure. Theproduct was distilled at 115°-125° C. and 5 mm of Hg to give 125.4 g(81% yield) of N-trimethylsilylmethyl benzylamine as a clear liquid; ¹ HNMR (CDCl₃) δ: 0.0 (s, 9H), 1.1 (br s, 1H), 2.01 (s, 2H), 3.76 (s, 2H),7.1-7.3 (m, 5H).

Step 4: N-Methoxymethyl-N-trimethylsilylmethyl Benzylamine

N-Trimethylsilylmethyl benzylamine (125.4 g, 0.649 mol), from Step 3,was added dropwise over a 10 minute period to a solution of 69.5 mL of37% aqueous formaldehyde at 0° C. After an additional 10 minutes, 75.2mL of methanol was added. The solution was then saturated with solidpotassium carbonate and stirred at 0° C. for 1 h. The layers wereseparated and the organic phase was stirred over solid potassiumcarbonate at ambient temperature for 18 h. The solution was filtered andfractionally distilled at 20 mm of Hg to give a 145°-155° C. fraction asa viscous oil, identified as N-methoxymethyl-N-trimethylsilylmethylbenzylamine. ¹ H NMR (CDCl₃) δ: 0.0 (s, 9H), 2.13 (s, 2H), 3.18 (s, 3H),3.71 (s, 2H), 3.96 (s, 2H), 7.1-7.3 (m, 5H).

Step 5:2-Benzyl-6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole

To a solution of 1.22 g (3.13 mmol) of5,6-dimethoxy-3-phenyl-2-sulfoxophenyl-3,4-dihydronaphthalene in 10 mLof methylene chloride was added 1 g (4.21 mmol) ofN-methoxymethyl-N-trimethylsilylmethyl benzylamine, from Step 4, and 0.1mL of trifluoroacetic acid. At 12 h intervals, the amine and acidadditions were repeated 7 more times. The solvent was then removed underreduced pressure with heating to 100° C. and the product waschromatographed on silica gel, eluted with 25% ethyl acetate in hexanesto give 0.14 g (11% yield) of2-benzyl-6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydrobenzo[e]isoindole; MSDCI: 398 (M+H)⁺ ; ¹ H NMR (CDCl₃) δ: 3.0-3.15 (m, 1H), 3.25-3.35 (m,1H), 3.45-3.55 (m, 3H), 3.62 (s, 3H), 3.65-3.7 (m, 2H), 3.8-3.9 (m, 2H),3.82 (s, 3H), 6.68 (m, 1H), 7.1-7.4 (m, 11H).

Step 6: 6,7-Dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1-H-benz[e]isoindolehydrochloride

To a solution of 1.0 g (2.52 mmol) of2-benzyl-6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindole,from Step 5, in 22 mL of 1,2-dichloroethane was added 0.11 g (0.05 mmol)of 1,8-bis(dimethylamino)-naphthalene and 0.33 mL (3.15 mmol) of1-chloroethyl chloroformate at 0° C. The solution was heated to refluxfor 2 h and the solvent removed in vacuo. The residue was filteredthrough silica gel eluted with 25% ethyl acetate in hexanes. Afterconcentration under reduced pressure, methanol (20 mL) was added and thesolution was heated to reflux for 30 minutes, before the solvent wasremoved in vacuo. The product was crystallized from ethanol/ether togive 0.46 g. (75% yield) of6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindolehydrochloride as a white solid.; MS DCI: 308 (M+H)⁺ ; ¹ H NMR (d₆ -DMSO)δ: 3.05-3.25 (m, 2H), 3.55 (s, 3H), 3.80 (s, 3H), 3.88 (m, 1H), 4.0-4.15(m, 2H), 4.25-4.45 (m, 2H), 6.91 (m, 1H), 7.15-7.3 (m, 3H), 7.4-7.6 (m,3H).

Step 7: 6,7-Dihydroxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindoleFormic Acid Salt

A suspension of 54.5 mg (0.159 mmol) of6,7-dimethoxy-4-phenyl-2,3,4,5-tetrahydro-1H-benz[e]isoindolehydrochloride, from Step 6, in 2 mL of methylene chloride was cooled to-78° C. and 0.64 mL of a 1M solution of boron tribromide in methylenechloride was added. The reaction was warmed to ambient temperature for 1h and cooled to -78° C. before 1 mL of methanol was added. After warmingto ambient temperature for 1 h, the solvents were removed in vacuo.Additional methanol (5 mL) was added and removed in vacuo. The productwas chromatographed on silica gel eluted with ethyl acetate/formicacid/water (18:1:1) to give 29.8 mg (58% yield) of the title compound asan off-white powder, m.p. 144° C.; MS DCI: 279 (M+H)⁺ ; ¹ H NMR (d₆-DMSO) δ: 2.95-3.15 (m, 2H), 3.6-3.9 (m, 3H), 4.1-4.3 (m, 2H), 6.43 (d,1H, J=7.5 Hz), 6.62 (d, 1H, J=7.5 Hz), 7.1-7.3 (m, 5H), 8.3 (s, 1H).

EXAMPLE 185A[1,3-cis]3-(1'-Adamantyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran(Method A)

A mixture of 185 mg (0.5 mmol)of1-(1'-adamantyl)-2-(spiro-[(1,3-benzo-dioxole)-2,1'-cyclohexane])-1-ethanol(from Example 179 Step 4 above), 110 mg (0.83 mmol)N-formyl-acetaldehyde dimethyl acetal and 46 mg (0.13 mmol) of zinctriflate in 3.0 mL of dry 1,2-dichloroethane was heated at reflux undera nitrogen atmosphere for 18 h. The reaction mixture was allowed to coolto ambient temperature and the reaction was quenched with ˜30 mL ethylacetate and saturated aqueous sodium bicarbonate solution. The organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate, filtered and concentrated to an oil. The oil was trituratedwith methanol to give 191 mg (87% yield) of the title compound as asolid, m.p. 182°-184° C.

EXAMPLE 185B[1,3-cis]3-(1'-Adamantyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran(Method B)

To a mixture of 94 mg (0.26 mmol) of1-(1'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol(from Example 59 Step 2 above), and 100 mg (0.75 mmol)ofN-formylacetaldehyde dimethyl acetal in 2.0 mL of dry acetonitrile wasadded 3 μL (˜0.1 equivalent) of methanesulfonic acid and the reactionmixture was heated at reflux for 12 h. The mixture was cooled to 0° C.The solid was removed by filtration, washed with cold acetonitrile anddried to give 79 mg (70% yield) of the title compound as a beige solid,m.p. 185°-187° C.

EXAMPLE 185C[1,3-cis]37(1'-Adamantyl)-5,6-cyclohexylidenedioxy,3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran(Method C)

To a mixture of 50 mg (0.14 mmol) of1-(1'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol(from Example 59 Step 2 above), and 60 mg (0.45 mmol) ofN-formylacetaldehyde dimethyl acetal was added a solution of 3 mg ofpolyphosphoric acid in ˜0.5 mL of acetonitrile. The reaction mixture washeated at reflux for 48 h and then was cooled to 0° C. for 0.5 h andfiltered. The solid was washed with cold acetonitrile and dried to give10.9 mg (18% yield) of the title compound as an off-white solid, m.p.185°-187° C.

EXAMPLE 185D[1,3-cis]3-(1'-Adamantyl)-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzopyran(Method D)

To a mixture of 181 mg (0.5 mmol) of1-(1'-adamantyl)-2-(spiro-[(1,3-benzodioxole)-2,1'-cyclohexane])-1-ethanol(from Example 59 Step 2 above), and 107 mg (0.83 mmol) ofN-formylacetaldehyde dimethyl acetal was added 25 μL of a 1.0M asolution of trimethylsilyl triflate in methylene chloride. The reactionmixture was heated at reflux for 4 h and then was cooled to 0° C. for0.5 h and filtered through a sintered glass funnel. The solid was washedwith cold acetonitrile and dried to give 198 mg (92% yield) of the titlecompound as a white solid, m.p. 187°-189° C.

EXAMPLE 186[1,3-cis]1-Aminomethyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzothiopyranHydrochloride Step 1:1-Phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]ethanol

Following the procedure of Example 47, Step 2, replacing the3,3-dimethyl-1,2-epoxybutane with styrene oxide, the title compound wasprepared and taken directly to the next step.

Step 2.S-Acetyl-1-phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]ethanethiol

A solution of triphenylphosphine (1.86 g, 7.09 mmol) in 50 mL of dry THFwas cooled to 0° C. Diisopropylazodicarboxylate (1.43 g, 7.09 mmol) wasadded dropwise via syringe and the reaction mixture was stirred at 0° C.for 30 min. A solution of 1.10 g (3.54 mmol) of1-phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]ethanol, from Step 1, andthiolacetic acid (0.67 g, 8.86 mmol) in 5 mL of THF was then addeddropwise to the reaction mixture. The reaction mixture was stirred at 0°C. for 1 hour, warmed to ambient temperature and stirred for 1 hour atambient temperature. The solvent was removed under reduced pressure, andthe residue was purified by flash chromatography on silica gel elutedwith 3% ethyl acetate in hexane to give 0.82 g (63% yield) of the titleproduct as a colorless oil. MS (DCI/NH₃): 369 (M+H)⁺, 386 (M+NH₄)⁺.

Step 3. 1-Phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]-ethanethiol

The thiolacetate from step 2 was dissolved in 10 mL of anhydrous diethylether. The resultant solution was added dropwise to a solution oflithium aluminum hydride (2.2 mmol) in 15 mL of diethyl ether. Afterstirring for 15 min at ambient temperature the reaction was quenched bythe careful addition of 20 mL of 1N aqueous hydrochloric acid solution.The diethyl ether layer was separated, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford 680 mg of thetitle product as a colorless oil. MS (DCI/NH₃): 327 (M+H)⁺, 344(M+NH₄)⁺.

Step 4.[1,3-cis]3-Phenyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzothiopyran

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) (61 mg, 0.28 mmol) wasadded dropwise to a stirred solution of 0.600 g (1.84 mmol) of1-phenyl-2-[3-(1,2-cyclohexylidenedioxy)pheny]ethanethiol, from step 3above, and 0.388 g (2.94 mmol) of N-formylaminoacetaldehyde dimethylacetal in 10 mL of anhydrous acetonitrile. The reaction was heated atreflux for 1 hour, then cooled and diluted with 50 mL of ethyl acetate.This solution was washed with 10% aqueous sodium carbonate solution,saturated NaCl solution, dried over anhydrous magnesium sulfate andconcentrated in vacuo to a brown oil. The residue was purified by flashchromatography on silica gel eluted with 40% ethyl acetate/hexane toafford 357 mg of the title product as a white solid. MS (DCI/NH₃): 396(M+H)⁺, 413 (M+NH₄)⁺.

Step 5.[1,3-cis]1-Aminomethyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzothiopyranHydrochloride

To a solution of 174 mg of the formamide compound from step 4 in 2 mL ofTHF and 2 mL of methanol was added 1 mL of 15% NaOH solution. Themixture was heated to reflux and stirred for 4 hours. The reaction wascooled, diluted with 15 mL of ethyl acetate, and the layers separated.The aqueous layer was extracted with 10 mL of ethyl acetate. The organiclayers were combined, washed with water and brine, dried over magnesioumsulfate and concentrated in vacuo to yield 145 mg of the free amineproduct as a colorless oil. The oil was Is dissolved in 3 mL of absoluteethanol, and 3 mL of 18% HCl in ethanol was added. The mixture washeated at reflux for 5 hours and cooled at 5° C. for 64 hours. Theprecipitate was filtered, washed and dried in vacuo at 50° C. to afford30 mg of the title product as a white solid. mp 230° C. (dec). MS (FAB):288 (M+H)⁺. ¹ H NMR (CD₃ OD) δ: 2.98 (dd, 1H), 3.31-3.35 (m, 2H), 3.65(dd, 1H), 4.14 (dd, 1H), 4.24 (dd, 1H), 6.67 (d, 1H), 7.2-7.5 (m, 5H).Anal calc'd. for C₁₆ H₁₈ ClNO₂ S: C, 59.34; H, 5.60; N, 4.33; found: C,59.56; H, 5.73, N, 4.26.

EXAMPLE 187[1,3-cis]1-(N-Methyl)aminomethyl-3-phenyl-3,4-dihydro-5,6-dihydroxy-1H-2-benzothiopyranHydrochloride

To a solution of 139 mg (0.35 mmol) of3-phenyl-5,6-cyclohexylidenedioxy-3,4-dihydro-1-(N-formyl)aminomethyl-1H-2-benzothiopyran,from Example 186 Step 4, in 4 mL of anhydrous THF was added 27 mg (0.70mmol) of LAH (0.7 mL of 1N LAH in THF). The reaction was stirred andheated to reflux for 1.5 hours. The reaction was cooled to 0° C.,diluted with 10 mL of ether and quenched by the careful addition ofwater (0.028 mL), 15% NaOH solution (0.028 mL), and water (0.084 mL). Tothis mixture was added a small amount of magnesium sulfate, and themixture was filtered to give an ether solution of the product. Thesolvent was removed in vacuo to afford 125 mg of the free base as acolorless oil. The oil was dissolved in 2 mL of absolute ethanol, and 3mL of 18% HCl in ethanol was added. The reaction was heated to refluxfor 2 hours, cooled, concentrated to 2 mL, and diluted with ether. Awhite precipitate which formed upon standing was collected byfiltration, washed with ether and dried in vacuo to afford 75 mg of thetitle product. mp 230° C. (dec). MS (FAB): 302 (M+H)⁺. ¹ H NMR (CD₃ OD)δ: 2.65 (s, 3H) 2.9 (dd, 1H), 3.25 (dd, 1H), 3.38 (dd, 1H), 3.64 (dd,1H), 4.12 (dd, 1H), 4.26 (dd, 1H), 6.65 (d, 1H), 6.7 (d, 1H), 7.2-7.5(m, 5H). Anal calc'd. for C₁₇ H₂₀ ClNO₂ S: C, 60.44; H, 5.97; N, 4.15;found: C, 60.17; H, 5.97, N, 4.10.

EXAMPLE 1881'-Aminomethyl-5',6'-dimethoxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'H-naphthalene)]HydrobromideStep A. 2,3-Dimethoxybenzyl Bromide

To a stirred solution of 2,3-dimethoxybenzyl bromide (25 g, 148 mmol,Aldrich) in 500 mL anhydrous ether was added PBr₃ (7 mL, 74 mmol), viasyringe. The resulting solution was stirred at room temperature for 2hours. The reaction was quenched by the addition of cold water. Thelayers were separated and the ether layer was washed with water, Na₂ CO₃solution, water and brine. The ether layer was then dried over MgSO₄,filtered, and evaporated to give 34 g (100% yield) of the title productas a low melting white solid.

Step B. Ethyl 1-(2,3-dimethoxybenzyl)cycloheptane Carboxylate

To a stirred solution of ethyl cycloheptane carboxylate (14 g, 82.4mmol, prepared by esterification of the acid, which was obtained fromAldrich, by refluxing in ethanol in the presence of an acid catalyst),in 600 mL anhydrous THF cooled to -78° C. was added 60 mL of 1.5M LDA(monotetrahydrofuran in hexane, Aldrich) via syringe. The resultinglight yellow reaction solution was stirred at -78° C. for 45 min and thebenzyl bromide (from step A above) was added (19 g dissolved in 75 mL ofTHF, 82.4 mmol). The reaction was stirred at -78° C. for 4 hours, thenit was quenched by addition of sat'd. NH₄ Cl, water and ether. Thelayers were separated, and the organic layer was washed with 1M HCl,water, and brine. The organic layer was dried over MgSO₄, filtered, andevaporated to yield a light amber oil (28 g) which was used withoutfurther purification.

Step C. [1-(2,3-dimethoxybenzyl)cycloheptyl]methanol

The crude ester (26 g, 82 mmol, from Step B above), was dissolved in 400mL anhydrous THF to which was added solid LiAlH4 (4.6 g, 123 mmol) insmall portions at room temperature. The reaction was stirred at roomtemperature until TLC indicated completion. The reaction was thenquenched with 1M HCl and diluted with ether. The layers were separated,and the organic layer was washed with 1M HCl, water, and brine. Theorganic layer was dried over MgSO₄, filtered and evaporated. Theresulting oil was purified by silica gel chromatography to give 20 g ofthe title product as a colorless oil.

Step D. 1-(2,3-dimethoxybenzyl)cycloheptane Carbaldehyde

The alcohol from Step C above (25 g, 89 mmol) was dissolved in 500 mL ofanhydrous DMSO. To this solution was added Et₃ N (50 mL, 358 mmol). ThenSO₃.Pyridine (57 g, 358 mmol), was dissolved in 400 mL of DMSO, and thissolution was added to the reaction vessel. The solution was then stirredat room temperature for two hours. The reaction solution was then pouredover ice and the resulting mixture was warmed to room temperature andextracted with CH₂ Cl₂. The organic layer was washed with 1M HCl, water,and brine, then the organic layer was dried over MgSO₄, filtered andevaporated. The crude product was chromatographed on silica gel, elutingwith 10:1 hexane:EtOAc to give the title product as a colorless oil (20g, 81% yield).

Step E. 2-[1-(2,3-dimethoxybenzyl)cycloheptymethylene-[1,3]-dithiane

To a solution of TMS-dithiane (18 mL, 94 mmol, Aldrich) in 500 mL ofanhydrous THF cooled to -78° C. was added nBuLi (37.5 mL of a 2.5M solnin hexane, 94 mmol), slowly via syringe. The resulting solution wasstirred at -78° C. for 30 min. and the aldehyde from Step D above (20 g,72 mmol) was added as a solution in 50 mL of anhydrous THF. The reactionsolution was then stirred for 1 h at -78° C. The reaction was quenchedwith sat'd. NH₄ Cl at room temperature and diluted with ether. Theresulting layers were separated, and the organic layer was washed with1M HCl, water and brine. The organic layer was then dried over MgSO₄,filtered and evaporated to give 27 g (100% yield) of the title product,which was used without further purification.

Step F.5,6'-Dimethoxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'H-naphthalene)]-1'-one

The crude product from Step E above (27 g, 72 mmol) was dissolved in 500mL of 5% aq. MeCN. To this solution was added HgCl₂ (39 g, 144 mmol) inone portion. The resulting suspension was refluxed for 1 hour, cooled toroom temperature, filtered and the filtrate evaporated to a solid. Thesolid was dissolved in 500 mL CH₂ Cl₂, which was washed with 1M HCl,water, dried over MgSO₄, filtered, evaporated and chromatographed(silica gel, 6:1 hexane/EtOAc) to give the spirotetralone title product(15 g).

Step G.1'-Aminomethyl-5',6'-dimethoxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'H-naphthalene)]hydrochloride

Following the procedure of Example 2, Steps 1 and 2, the compound fromStep F above was reacted and the title product was isolated.

Step H.1'-Aminomethyl-5,6'-dihydroxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'-H-naphthalene)]hydrobromide

Following the procedure described in Example 2, Step 3, the titlecompound was prepared. mp 157°-8° C. MS (DCI) M/Z: 274. anal. calc. forC₁₇ H₂₄ BrNO₂ : C, 57.63; H, 6.82; N, 3.95; found: C, 57.70; H, 6.80; N,3.97.

                                      TABLE 9                                     __________________________________________________________________________    Examples 189-198                                                                                                                Elemental Analysis          Ex. No.                                                                             Compound*            Ester         mp °C.                                                                      MS**                                                                              C      H  N                 __________________________________________________________________________    189                                                                                  ##STR233##                                                                                         ##STR234##   140-2                                                                              260 c: 57.62 f:                                                                          7.04 7.15                                                                        3.65 3.47         190                                                                                  ##STR235##                                                                                         ##STR236##   263-4                                                                              248 c: 54.89 f:                                                                          6.76 6.83                                                                        4.27 4.38         191                                                                                  ##STR237##                                                                                         ##STR238##   285-6                                                                              288 c: 59.82 f:                                                                          7.23 7.27                                                                        3.48 3.54         192                                                                                  ##STR239##                                                                                         ##STR240##   174-5                                                                              276 c: 57.02 +0.1 H.sub.2 O                                                       : 56.64                                                                              7.37 7.38                                                                        3.91 2.87         193                                                                                  ##STR241##                                                                                         ##STR242##   240-1                                                                              276 c: 57.02 +0.1 H.sub.2 O                                                       : 56.86                                                                              7.37 7.07                                                                        3.91 3.87         194                                                                                  ##STR243##                                                                                         ##STR244##   176-8                                                                              262 c: 55.27 f:                                                                          7.13 6.87                                                                        4.03 3.99         195                                                                                  ##STR245##                                                                                         ##STR246##   242-3                                                                              250 c: 54.55 f:                                                                          7.32 7.43                                                                        4.24 4.25         196                                                                                  ##STR247##                                                                                         ##STR248##   210-1                                                                              248 c: 52.86 f:                                                                          6.92 6.77                                                                        4.11 3.95         197                                                                                  ##STR249##                                                                                         ##STR250##   182-3                                                                              290 c: 58.38 f:                                                                          7.62 7.70                                                                        3.78 4.02         198                                                                                  ##STR251##                                                                                         ##STR252##   242-4                                                                              278 c: 55.05 +0.2 CH.sub.2                                                        Cl.sub.2 f:                                                                          7.62 7.46                                                                        3.73 3.64         __________________________________________________________________________     *As the HBr salt unless indicated otherwise (FB = free base); all             compounds 1-3 cis unless indicated otherwise                                  ***DCl MS (M + H)+-                                                      

EXAMPLES 189-198

Following the synthesis outlined in Example 188, using the appropriateester as indicated, Examples 189 to 192 were made, as their HBr salts,as shown above in Table 9 The structure of each was confirmed by meltingpoint, mass spectrum and elemental analysis as designated.

Examples 193 to 198 were prepared, using the appropriate ester, asdescribed in Example 188, hydrogenated and deprotected as described inExample 35 as their HBr salts, as shown above in Table 9. The structureof each was confirmed by melting point, mass spectrum and elementalanalysis as designated.

EXAMPLE 199Spiro[cycloheptane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]-7',8'-diolHydrobromide Step A.5',6'-Dimethoxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'H-naphthalene)]aceticAcid Ethyl Ester

A stirred solution of5',6'-dimethoxyspiro[cycloheptane-1,3'-(3',4'-dihydro-2'H-naphthalen)]-1'-one,from Step F of Example 188 above, (15.75 g, 54.5 mmol) in 500 mL ofanhydrous THF was cooled to -78° C. To this solution was added 1M LDA inTHF via cannula (60 mL, 60 mmol). The reaction was stirred at -78° C.for 45 min and ethylbromoacetate (6.34 mL, 57.2 mmol) was added viasyringe. The resulting reaction solution was slowly warmed to roomtemperature and stirred for an additional 24 hours. The reaction wasquenched by the addition of sat'd. NH₄ Cl, then water, and diluted withether. The organic layer was separated and washed with 1M HCl, water andbrine, dried over MgSO₄, filtered, evaporated and chromatographed onsilica gel eluting with 7:1 hexane:EtOAc to furnish the title product asa light amber oil (7.6 g).

Step B.9b'-Cyano-5',6'-dimethoxyspiro[cycloheptane-1,4'-(3'a,4,5,9b-tetrhydro-3H-naphtho[1',2'-b]furan)]-2'-one

To a stirred solution of the ester from Step A above (16 g, 42.8 mmol)in 500 mL of anhydrous toluene was added 1M Et₂ AlCN in toluene (86 mL,86 mmol) quickly via syringe. The resulting reaction solution wasstirred for 2 hours. The reaction was poured into 400 mL of ice cold 2MHCl, diluted with ether, and the organic layer separated and washed with1M HCl, water and brine. The organic layer was then dried over MgSO₄,filtered and evaporated to yield the tricyclic lactone title product asa light yellow solid (15 g, 100% yield).

Step C.1'-Aminomethyl-5',6'-dimethoxy-1'-hydroxyspiro[cycloheptane-1,3'-(1',2',3',4'-tetrahydronaphthalene)]-2-ethanol

To a stirred solution of the tricyclic lactone (15 g, 42.3 mmol, fromStep B above) in 500 mL of anhydrous THF was added LiAlH4 (6.4 g, 169mmol) in portions, causing the THF to reflux. The THF was refluxed for 2hours then cooled to room temperature, transferred to a 2L Erlenmeyerflask, diluted with 200 mL of THF and quenched with solid Na₂ SO₄.10H₂O. After the quench was completed, celite filter aid was added to theslurry, and the slurry was filtered over celite, the filter cake waswashed with warm THF, and the filtrate was evaporated under reducedpressure to yield 12 g of crude product as an off-white solid. The crudeproduct was triturated with a minimal amount of CH₂ Cl₂ and filtered toyield 6.3 g of the title product as a fluffy white solid. The filtratewas concentrated and purified by column chromatography eluting with89:9:1 CH₂ Cl₂ : MeOH:NH₄ OH diluted to 150% of its volume with CH₂ Cl₂)to yield another 3.6 g. (Total yield: 65%).

Step D.7',8'-Dimethoxyspiro[cycloheptane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]

To a stirred solution of the product from Step C above (6.3 g, 17.36mmol) in 170 mL of anhydrous CH₂ Cl₂ cooled to -78° C. was added PBr₃(4.9 mL, 52.1 mmol) slowly via syringe. The cooling bath was removed andthe reaction was stirred at room temperature for 48 hours, and the CH₂Cl₂ was then evaporated. The resulting oil was partitioned between 200mL of ethyl acetate and 200 mL of 50% ammonium hydroxide/water. Thelayers were separated, and the aqueous layer was washed with EtOAc. Theorganic layers were combined and washed with water, dried over MgSO₄,filtered and evaporated to furnish 3 g of crude title product. Theproduct was purified by column chromatography on silica gel, elutingwith 89:9:1 CH₂ Cl₂ : MeOH:NH₄ OH diluted with CH₂ Cl₂ 60:40), to yieldpure title product (2.4 g, 42% yield).

Step E.Spiro[cycloheptane-1,5'-(1',2',3',4',5',6'-hexahydrobenzo[h]isoquinoline)]-7',8'-diolHydrobromide

To a stirred solution of the compound from Step D (1.5 g, 4.59 mmol) inanhydrous CH₂ Cl₂ cooled to -78° C. was added 1M BBr₃ in CH₂ Cl₂ (9.2mL, 9.2 mmol) slowly via syringe. The cooling bath was removed and thereaction solution was warmed to room temperature. The reaction solutionwas again cooled to -78° C. and quenched with 100 mL of absolutemethanol. The reaction solution was evaporated to a residue which wasre-dissolved with 100 mL of absolute methanol and heated to reflux on asteam bath. The solution was then cooled to room temperature by bubblingnitrogen into the solution. The solvent was removed under reducedpressure to provide a residue which was triturated with CH₂ Cl₂ toprecipitate the

                                      TABLE 10                                    __________________________________________________________________________    Examples 200-209                                                                                                                  Elemental Analysis        Ex. No.                                                                            Compound*              Ester         mp ° C.                                                                     MS** C    H  N                 __________________________________________________________________________    200                                                                                 ##STR253##                                                                                           ##STR254##   268-70                                                                             294  c: 60.97 f:60.84                                                                   5.39 5.39                                                                        3.74 3.77         201                                                                                 ##STR255##                                                                                           ##STR256##   229-231                                                                            294  c: 60.97 f:60.81                                                                   5.39 5.35                                                                        3.74 3.74         202                                                                                 ##STR257##                                                                                           ##STR258##   236-7                                                                              300  c: 60.00 f:60.08                                                                   6.89 6.95                                                                        3.68 3.72         203                                                                                 ##STR259##                                                                                           ##STR260##   na   274  c: f:na                   204                                                                                 ##STR261##                                                                                           ##STR262##   279-281                                                                            272  c: 56.52 f:56.48                                                                   6.72 6.18                                                                        3.88 3.73         205                                                                                 ##STR263##                                                                                           ##STR264##   274-5                                                                              286  c: 56.26 f:56.27                                                                   6.82 6.86                                                                        3.65 3.43         206                                                                                 ##STR265##                                                                                           ##STR266##   279-280                                                                            300  c: 60.00 f:59.87                                                                   6.89 6.72                                                                        3.68 3.50         207                                                                                 ##STR267##                                                                                           ##STR268##   184-6                                                                              314  c: 58.70 f:59.03                                                                   7.11 7.23                                                                        3.80 3.61         208                                                                                 ##STR269##                                                                                           ##STR270##   248-9                                                                              302  c: 57.26 +0.2 HBr                                                             f:57.42                                                                            7.13 7.00                                                                        3.51 3.41         209                                                                                 ##STR271##                                                                                           ##STR272##   229-230                                                                            300  c: 60.00 f:60.09                                                                   6.89 6.93                                                                        3.68 3.56         __________________________________________________________________________     *As the HBr salt unless indicated otherwise (FB = free base)                  ***DCl MS (M + H)+-                                                      

product. The product was filtered and dried in a vacuum oven at 55° overnight to furnish the title product as a white solid (1.3 g, 76% yield).mp 288-290. MS (DCI) M/Z: 300. anal. calc. for C₁₉ H₂₅ NO₂.HBr.0.5 H₂ O:C, 58.35; H, 7.00; N, 3.58; found: C, 58.55; H, 7.07; N, 3.46.

EXAMPLES 200-209

Following the synthesis outlined in Example 199, using the appropriatetetralone, Examples 200-209 were made as their HBr salts, as shown abovein Table 10. The structure of each was confirmed by melting point, massspectrum and elemental analysis as designated.

EXAMPLE 2102-Methyl-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diolHydrobromide Step A.7,8-Dimethoxy-2-formyl-5-phenyl-1,2,3,4,5,6-hexahydro-benzo[h]isoquinoline

To a solution of the free base7,8-dimethoxy-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline, (390mg, 1.2 mmol, from Example 200) in THF (25 mL) was added ethyl formate(40 mL). The resulting solution was heated at reflux for 17 hours,concentrated, and the concentrate was chased with THF. The crude productwas used directly in the next step.

Step B.7,8-Dimethoxy-2,methyl-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline

To a solution of the compound from Step A (1.2 mmol) in THF (25 mL) wasadded LAH (60 mg, 1.6 mmol). The reaction was refluxed for 3 hours,diluted to 300 mL with THF, quenched with excess sodium sulfatedecahydrate, and filtered over celite. The filtrate was concentratedthen subjected to flash chromatography on silica gel with NH₄OH/MeOH/EtOAc/CH₂ Cl₂ (1:4:50:50) as the eluting solvent to give thetitle product (270 mg, 67% yield).

Step C.2-Methyl-5-phenyl-1,2,3,4,5,6-hexahydrobenzo[h]isoquinoline-7,8-diolHydrobromide

To a solution of the free base from Step B above (270 mg, 81 mmol) inacetic acid (30 mL) was added 48% HBr (28 mL). The resulting solutionwas heated at reflux for 6 hours, cooled and concentrated in vacuo to 5mL. This concentrate was chased with ethanol, methanol and heptane untildry. The product was dried under vacuum overnight and then crystallizedfrom MeOH/Et₂ O to afford 230 mg (73% yield) of the title product as atan powder. Analysis calculated for C₂₀ H₂₂ BrNO₂ (0.2 H₂ O): C, 61.30;H, 5.76; N,3.57. Found: C, 61.30; H, 5.67; N, 3.44. MS DCI/NH3 M/Z: 308(M+H)⁺. Melting point: 259°-261°.

EXAMPLES 211-212

Following the synthesis outlined in Example 210, using the appropriatespiro aldehyde, Examples 211 and 212 were made as their HBr salts, asshown below in Table 11. The structure of each was confirmed by meltingpoint, mass spectrum and elemental analysis.

                                      TABLE 11                                    __________________________________________________________________________    Examples 211-212                                                                                              Elemental Analysis                            Ex. No.                                                                            Compound*         mp ° C.                                                                     MS**                                                                              C   H  N                                      __________________________________________________________________________    211                                                                                 ##STR273##       163-5                                                                              286 c: 59.02 f:59.11                                                                  6.60 6.58                                                                        3.82 3.79                              212                                                                                 ##STR274##       289-290                                                                            300 c: 58.08 f:57.81                                                                  7.03 6.73                                                                        3.57 3.43                              __________________________________________________________________________     *As the HBr salt unless indicated otherwise (FB = free base)                  ***DCl MS (M + H)+-                                                      

EXAMPLE 2131-Acetylaminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene

Approximately 1 mmol of1-aminomethyl-3-phenyl-5,6-dihydroxy-3,4-dihydronaphthalene, fromExample 2, was reacted with 1.2 mmol of acetic anhydride in the presenceof 1.2 mmol of triethylamine in an excess of methylene chloride. Themixture was washed with 0.1N HCl, and dried. The product wasprecipitated by addition of ether, collected, and dried. mp 238° C. MSM/Z: 310. Anal. calc. for C₁₉ H₁₉ NO₃.HBr C: 65.03; H, 5.72; N, 3.61;found: C, 73.46; H, 6.13; N, 4.49.

EXAMPLE 2141-Aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranHydrochloride Step 1. Diphenylmethylenedioxybenzene

Catechol (14.7 g, 0.134 mol, Aldrich Chemical Co.) was placed in a3-neck flask flushed with Argon. The flask was immersed in a 180° C. oilbath, the catechol allowed to melt, and neat dichlorophenylmethane (24.6mL, 0.134 mol) was carefully added in small portions, with resultingvigorous gas evolution. Heating was continued for an additional 10 min,the lo flask was cooled, and the crude product was dissolved in 300 mLof ether. The organic layer was separated and washed with 1N NaOH andbrine, dried over MgSO₄ and concentrated in vacuo to give a yellowsolid. The crude product was triturated with 5% ethyl acetate in hexane,which was filtered to yield 13.1 of an off-white solid. A second cropwas obtained, and the total yield was 24.8 g (68% yield) of the titlecompound. MS (DCI/NH₃) M/Z: 275 (M+H)⁺. ¹ H NMR (CDCl₃, 300 MHz) δ:6.8-6.9 (m, 4H), 7.3-7.45 (m, 6H), 7.5-7.65 (m, 4H).

Step. 2. (2S )-3-chloro-1-(2,3-diphenylmethylenedioxyphenyl)-2-propanol

n-Butyl lithium (2.3 mL of a 9.5M solution in hexane, 22 mmol) was addeddropwise to a solution of 5.47 g of diphenylmethylenedioxybenzene (fromstep 1) in 75 mL of THF at 0° C. After 5 hr the solution was cooled to-78° C., and a solution of 1.85 g (20 mmol) of (S)-(+)-epichlorohydrin(Aldrich Chemical Co.) in 10 mL of THF was added. Boron trifluorideetherate (2.4 mL, 20 mmol) was then added dropwise, and the reaction wasstirred for 1.5 hr. The reaction was quenched by addition of 50 mL ofsaturated NaHCO₃, and the mixture was warmed to ambient temperature andpartitioned between 100 mL of ether and 100 mL of water. The aqueousphase was extracted with ether (2×40 mL), and the ether extracts werecombined and washed with brine, dried over MgSO₄ and concentrated invacuo to give a brown oil, which was purified by flash chromatographyover silica gel, eluting with 15% ethyl acetate in hexane, to affordafter removal of the solvent 4.23 g of the title compound as a lightyellow oil (58% yield). MS (DCI/NH₃) M/Z: 367 (M+H)⁺, 384 (M+NH₄)⁺. ¹ HNMR (CDCl₃, 300 MHz) δ: 2.3 (d, 1H), 2.9-3.0 (m, 2H), 3.5 (dd, 1H), 3.6(dd, 1H), 4.1-4.23 (m, 1H), 6.65-6.85 (m, 3H), 7.37 (m, 6H), 7.55 (m,4H).

Step 3. (2S)-3-(2,3-diphenylmethylenedioxyphenyl-1,2-epoxypropane

A 15% aqueous NaOH solution (60 mL) was added to a solution of 9.51 g(25.9 mmol) of(2S)-3-chloro-1-(2,3-diphenylmethylenedioxyphenyl)-2-propanol (from step2 above) in 180 mL of 2:1: ether:methanol. The mixture was stirredvigorously and heated to reflux for 3 hr. The reaction was poured into100 mL of water, and the aqueous phase was extracted with ether (2×75mL). The combined organic extracts were washed with brine, dried overMgSO₄ and concentrated in vacuo to give 8.35 g of the title compound asa light brown oil. This material was taken directly to the next step. MS(DCI/NH₃) M/Z: 331 (M+H)⁺, 348 (M+NH₄)⁺.

Step 4. (2R)-4,4-Dimethyl-(2,3-diphenylmethylenedioxyphenyl)-2-pentanol

t-Butyl lithium (21.4 mL of a 1.7M solution in pentane, 36.4 mmol) wasadded dropwise to a suspension of CuCN (1.63 g, 18.2 mmol) in 120 mL ofTHF at -78° C. The mixture was stirred for 30 min and allowed to warm to-10° C. A soultion of 8.01 g(2S)-3-(2,3-diphenylmethylenedioxyphenyl)-1,2-epoxypropane (24.2 mmol)of (from step 3 above) in 20 mL of THF was added dropwise. The reactionswas stirred for 18 hr, then quenched by addition of 100 mL of 9:1saturated NH₄ Cl: conc. NH₄ OH. The mixture was stirred vigorously for30 min and partitioned between 50 mL of water and 150 mL of ether. Theaqueous phase was extracted twice with 50 mL of ether, and the combinedlayers were washed with water and saturated NH₄ Cl and dried over MgSO₄.The solvents were removed under vacuum to give an amber oil. The oil waspurified by flash chromatography over silica gel, eluting with 20% ethylacetate:hexane to afford 5.95 g (63% yield) of the title compound as ayellow oil. MS (DCI/NH₃) M/Z: 389 (M+H)⁺, 406 (M+NH₄)⁺. ¹ H NMR (CDCl₃,300 MHz) δ: 0.95 (s, 9H), 1.45 (m, 2H), 2.73 (dd, 1H), 2.85 (dd, 1H),4.08 (m, 1H), 6.65-6.8 (m, 3H), 7.37 (m, 6H), 7.57 (m, 4H).

Step 5.1-aminomethyl-3-(2,2-dimethylpropyl)-5,6-diphenylmethylenedioxy-3,4-dihydro-1H-2-benzopyranHydrochloride

Following the procedures of steps 5 and 6 of Example 179, the(2R)-4,4-Dimethyl-1-(2,3-diphenylmethylenedioxyphenyl)-2-pentanolcompound from step 4 above was converted into the title product.

Step 6.1-aminomethyl-3-(2,2-dimethylpropyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyranHydrochloride

To as solution of1-aminomethyl-3-(2,2-dimethylpropyl)-5,6-diphenylmethylenedioxy-3,4-dihydro-1H-2-benzopyranhydrochloride, from step 5 above, in 50 ml of methanol, was added 210 mgof 10% Pd/C. The mixture was purged and hydrogenated at 1 atm for 18 hr.The catalyst was removed by filtration, and the filtrate wasconcentrated in vacuo, dissolved in 10 mL of 1N HCl, washed with ether,and taken to dryness. The residue was crystallized from ethanol/ether toafford 300mg of the title compound. mp 220° C. MS (DCI/NH₃) M/Z: 266(M+H)⁺, 283 (M+NH₄)⁺. ¹ H NMR (DMSO-d₆, 300 MHz) δ: 0.97 (s, 9H), 1.45(dd, 1H), 1.65 (dd, 1H), 2.32 (dd, 1H), 2.65 (dd, 1H), 2.87 (dd, 1H),3.38 (dd, 1H), 3.65 (m, 1H), 4.85 (m, 1H), 6.52 (d, 1H), 6.67 (d, 1H),7.8 (bs, 3H), 8.45 (bs, 1H), 9.28 (bs, 1H).

EXAMPLES 215-220

Following the synthesis outlined in Example 214, using the appropriateorganocuprate reagent, Examples 215 and 216 were prepared. Following thethe procedures described in Examples 214 and 111, Examples 217-219.Example 220 was prepared by the procedures described in Examples 214 and111, repeating the procedure of Example 111 in order to place the secondmethyl group on the amino function. The structures of Examples 215-220were confirmed by melting point, mass spectra and elemental analysis asdesignated. The data for examples 215-220 are shown below in Table 12.

EXAMPLES 221-230

Following the synthesis outlined in Examples 47 and 48, using theappropriate epoxide and the appropriate aldehyde diacetal, Examples221-223 were made as shown below in Table 13. The structure of each wasconfirmed by melting point (m.p), elemental analysis and mass spectra asdesignated.

Following the synthesis outlined in Examples 47, 48 and 111 using theappropriate epoxide and the appropriate aldehyde diacetal, Examples224-226 were made as disclosed in Table 13. The structure of each wasconfirmed by melting point (m.p), elemental analysis and mass spectra asdesignated.

Following the synthesis outlined in Examples 47, 48 and 111, andrepeating the procedure of Example 111, using the appropriate epoxideand the appropriate aldehyde diacetal, Examples 227-230 were made asdisclosed in Table 13. The structure of each was confirmed by meltingpoint (m.p), elemental analysis and mass spectra as designated.

EXAMPLES 231-237

Following the synthesis outlined in Example 188, using the appropriateester as indicated, Examples 231 to 234 were made, as their HBr salts,as shown below in Table 14 The structure of each was confirmed bymelting point, mass spectrum and elemental analysis as designated.

Examples 235 to 237 were prepared, using the appropriate ester, asdescribed in Example 188, hydrogenated and deprotected as described inExample 35, as their HBr salts, as shown below in Table 14. Thestructure of each was confirmed by melting point, mass spectrum andelemental analysis as designated.

                                      TABLE 12                                    __________________________________________________________________________    Examples 215-220                                                                                                Elemental Analysis                          Ex. No.                                                                            Compound*            mp ° C.                                                                    MS**                                                                              C    H  N                                   __________________________________________________________________________    215                                                                                 ##STR275##          na  278 na                                          216                                                                                 ##STR276##          189 252 c: 56.65 f:56.87 +0.55                                                             7.81 7.42                                                                        4.72 4.65                           217                                                                                 ##STR277##          230 dec                                                                           280 c: 59.16 f:59.15 +0.5                                                              8.34 8.01                                                                        4.31 4.19                           218                                                                                 ##STR278##          187 292 c: 61.27 f:61.00                                                                   8.05 7.66                                                                        4.20 4.06                           219                                                                                 ##STR279##          170 266 c: 56.94 f:57.13 +0.4                                                              7.77 7.70                                                                        4.34 4.64                           220                                                                                 ##STR280##          215 294 c: 60.90 f:60.79 +0.3                                                              8.60 8.34                                                                        4.18 4.19                           __________________________________________________________________________     *As the HCl salt unless indicated otherwise (FB = free base)                  ***DCl MS (M + H)+-                                                      

                                      TABLE 13                                    __________________________________________________________________________    Examples 221-230                                                                                                            Elemental Analysis              Ex. No.                                                                            Compound*             Epoxide** mp ° C.                                                                     MS***                                                                             C    H  N                       __________________________________________________________________________    221                                                                                 ##STR281##                                                                                          ##STR282##                                                                             >240 306 c: 62.26 f:61.88 +0.3                                                         H.sub.2 O                                                                          8.30 8.17                                                                        4.03 4.31               222                                                                                 ##STR283##                                                                                          ##STR284##                                                                             na   292 c: 62.28 f:62.29                                                                   7.99 8.05                                                                        4.27 4.09               223                                                                                 ##STR285##                                                                                          ##STR286##                                                                             na   354 c: 65.35 f:65.43 0.8                                                          H.sub.2 O                                                                          7.38 7.33                                                                        3.46 3.11               224                                                                                 ##STR287##                                                                                          ##STR288##                                                                             >215 dec                                                                           320 c: 63.16 f:63.00 +0.3                                                         H.sub.2 O                                                                          8.54 8.53                                                                        3.88 3.92               225                                                                                 ##STR289##                                                                                          ##STR290##                                                                             na   368 c: 66.90 f:66.80 +0.5                                                         H.sub.2 O                                                                          7.57 7.88                                                                        3.39 3.02               226                                                                                 ##STR291##                                                                                          ##STR292##                                                                             na   305 c: 63.24 f:62.92                                                                   8.25 8.27                                                                        4.10 3.91               227                                                                                 ##STR293##                                                                                          ##STR294##                                                                             222 (dec)                                                                          300 c: na f:na                      228                                                                                 ##STR295##                                                                                          ##STR296##                                                                             239 (d)                                                                            306 c: 61.62 f:61.59 +0.5                                                         H.sub.2 O                                                                          8.33 8.22                                                                        3.99 4.33               229                                                                                 ##STR297##                                                                                          ##STR298##                                                                             na   382 c: 66.95 f:66.75 +0.7                                                         H.sub.2 O                                                                          7.82 7.57                                                                        3.25 3.27               230                                                                                 ##STR299##                                                                                          ##STR300##                                                                             na   320 c: 63.80 f:63.70 +0.1                                                         H.sub.2 O                                                                          8.51 8.32                                                                        3.92 3.85               __________________________________________________________________________     *As the HCl salt unless indicated otherwise (FB = free base); all             compounds 1-3 cis unless indicated otherwise                                  **1 = commercially available,                                                 2 = synthesized by method A of Example 47,                                    3 = synthesized by Method B of Example 47;                                    4 = synthesized by Method C of Example 47.                                    ***DCl MS (M + H)+-                                                           ****Prepared by the procedure described in Examples 47, 48 and old 130        using (-)Bchlorodiidopinocamphorylborane                                 

                                      TABLE 14                                    __________________________________________________________________________    Examples 231-237                                                                                                                Elemental Analysis          Ex. No.                                                                             Compound*           Ester         mp ° C.                                                                      MS**                                                                              CHN                         __________________________________________________________________________    231                                                                                  ##STR301##         Adam-CH.sub.2COOEt                                                                          240 (dec)                                                                           326 c: 61.539.983.42                                                              f:61.22.293.09 +0.2                                                           H.sub.2 O                   232                                                                                  ##STR302##                                                                                        ##STR303##   210-1 302 c: 58.697.283.60                                                              f:58.72.193.71 +0.08                                                          HBr                         233                                                                                  ##STR304##         t-bu-(CH.sub.2).sub.2COOEt                                                                  140-3 262 c: 54.977.003.95                                                              f:55.34.783.57 +0.1                                                           MeOH + 0.1 CH.sub.2                                                           Cl.sub.2                    234                                                                                  ##STR305##                                                                                        ##STR306##   204-5 316 c: 59.397.503.46                                                              f:59.41.463.39 +0.1                                                           HBr                         235                                                                                  ##STR307##         Adam-CH.sub.2COOEt                                                                          254   328 c: 44.875.722.49                                                              f:44.73.813.58 +1.8                                                           HBr                         236                                                                                  ##STR308##                                                                                        ##STR309##   184-6 304 c: 56.977.603.50                                                              f:57.01.513.69 +0.2                                                           HBr                         237                                                                                  ##STR310##                                                                                        ##STR311##   146-8 318 c: 52.727.803.37                                                              f:57.77.733.39 +0.22        __________________________________________________________________________                                                      HBr                          *As the HBr salt unless indicated otherwise (FB = free base); all             compounds 1-3 cis unless indicated otherwise                                  ***DCl MS (M + H)+-                                                      

EXAMPLES 238-243

Following the synthesis outlined in Example 199, using the appropriatetetralone, Examples 238-243 were made as their HBr salts, as shown belowin Table 15. The structure of each was confirmed by melting point, massspectrum and elemental analysis as designated.

                                      TABLE 15                                    __________________________________________________________________________    Examples 238-243                                                                                                           Elemental Analysis               Ex. No.                                                                            Compound*           Ester       mp ° C.                                                                    MS**                                                                              CHN                              __________________________________________________________________________    238                                                                                 ##STR312##                                                                                        ##STR313## 226 352 c: 61.966.943.14 f:61.836.823                                                 .09 +0.2 HBr                     239                                                                                 ##STR314##                                                                                        ##STR315## na  294 c: 59.945.523.65 f:59.485.303                                                 .75 +0.5 H.sub.2 O               240                                                                                 ##STR316##                                                                                        ##STR317## 281-4                                                                             342 c: 59.327.633.01 f:59.097.403                                                 .01 +0.25 HBr + 0.25 EtOH        241                                                                                 ##STR318##                                                                                        ##STR319## 294-6                                                                             328 c: 60.007.783.18 f:59.977.493                                                 .16 +0.5 H2O + 0.5 EtOH          242                                                                                 ##STR320##                                                                                        ##STR321## 229-31                                                                            288 c: na f:na                       243                                                                                 ##STR322##         n-bu.CH.sub.2COOEt                                                                        125-30                                                                            274 c: na f:na                       __________________________________________________________________________     *As the HBr salt unless indicated otherwise (FB = free base)                  ***DCl MS (M + H)+-                                                      

                                      TABLE 16                                    __________________________________________________________________________    Examples 244-252                                                                                                               Elemental Analysis           No.  Compound*              Ester       mp °C.                                                                      MS**                                                                              C      N   N                 __________________________________________________________________________    244                                                                                 ##STR323##                                                                                           ##STR324## 276  288 c: 58.41 f: 58.09 +0.1                                                        H.sub.2 O                                                                            7.14 7.03                                                                         3.78 3.77         245                                                                                 ##STR325##                                                                                           ##STR326## 150-3                                                                              314 c: 44.19 f: 44.22 +0.8                                                        HBr + 0.5 H.sub.2                                                                    5.60 5.30                                                                         2.58 2.63         246                                                                                 ##STR327##                                                                                           ##STR328## na   308 c: 59.52 f: 59.60 +0.2                                                        HBr    5.72 5.57                                                                         3.47 3.45         247                                                                                 ##STR329##                                                                                           ##STR330## na   308 c: na f: na                  248                                                                                 ##STR331##                                                                                           ##STR332## 170-180d                                                                           342 c: 58.10 f: 58.24 +0.4                                                        HBr    7.18 7.21                                                                         3.08 2.94         249                                                                                 ##STR333##                                                                                           ##STR334## 155-7                                                                              314 c: 59.29 f: 59.09 +0.6                                                        H.sub.2 O                                                                            7.26 6.96                                                                         3.46 3.31         250                                                                                 ##STR335##                                                                                           ##STR336## 167-70d                                                                            328 c: na f: na                  251                                                                                 ##STR337##                                                                                           ##STR338## 119-21                                                                             328 c: 54.26 f: 54.48 +0.9                                                        CH.sub.2 Cl.sub.2                                                                    6.61 6.51                                                                         2.89 3.28         252                                                                                 ##STR339##                                                                                           ##STR340## 165-7                                                                              302 c: 51.41 f: 51.63 +1.0                                                        CH.sub.2 Cl.sub.2                                                                    6.47 6.49                                                                         3.00 3.01         __________________________________________________________________________     *As the HBr salt unless indicated otherwise (FB = free base)                  ***DCI MS (M + H)+-                                                      

EXAMPLES 244-250

Following the synthesis outlined in Examples 199 and 210, using theappropriate tetralone, Examples 244-250 were made as their HBr salts, asshown above in Table 16. The structure of each was confirmed by meltingpoint, mass spectrum and elemental analysis as designated.

EXAMPLE 251

Following the synthesis outlined in Examples 199 and 210, using theappropriate tetralone, and substituting acetic anhydride for the ethylformate of Example 210 followed by reduction with LAH, Example 251 wasmade as the HBr salt, as shown above in Table 16. The structure wasconfirmed by melting point, mass spectrum and elemental analysis asdesignated.

EXAMPLE 252

Following the procedure of Example 35, the compound of Example 206 washydrogenated, and the compound of Example 252 was isolated as the HBrsalt, as shown above in Table 16. The structure was confirmed by meltingpoint, mass spectrum and elemental analysis as designated.

EXAMPLE 253 Determination of Competitive Binding in D-1 and D-2 ReceptorBinding Assays

Homogenized rat caudate was incubated in the presence of [¹²⁵I]SCH-23982 (a selective antagonist of the dopamine D-1 receptor) andthe compounds of this invention, according to procedures described by A.Sidhu et al. in European J Pharmacology 113:437 (1985) and in European JPharmacology 128:213 (1986). The compounds compete with the radiolabeledligand for occupancy of the receptors and the molar potency of eachcompound was quantified. The affinity of the compound for the receptor(Ki) was calculated as described by Y. C. Cheng and W. H. Prusoff inBiochemical Pharmacology 22:3099 (1973) from the relationship Ki=IC₅₀(1+[L]/K_(D)) where IC₅₀ is the concentration of test compound whichproduces a 50% inhibition in the specific binding of the radioligand, L;[L] is the concentration of radioligand; and K_(D) is the affinity ofthe radioligand for the receptor.

The procedure for the dopamine D-2 receptor binding assay was similar tothat used for the D-1 receptor assay. Homogenized rat caudate was thesource of the D-2 receptors. The tissue homogenate was incubated in thepresence of [¹²⁵ I]-p-aminophenylethyl spiroperidol (a selectiveantagonist of the dopamine D-2 receptor) and the compounds beingevaluated, according to the protocol described by T. Agui, N. Amlaiky,M. G. Caron and J. W. Kebabian in Molecular Pharmacology, 33: 163(1988). The molar affinity of the compound for the receptor binding sitewas calculated by the same method used for the D-1 receptor assay,assuming a competitive interaction between the compound and theradiolabeled ligand.

The competitive binding data (Ki values) from the D-1 and D-2 receptorbinding assays are shown above in Table 17. The Ki values are inverselyproportional to the affinity of the compound for the receptor.

                  TABLE 17                                                        ______________________________________                                        Competitive Binding to D-1 and D-2 Receptors                                  Example #    D-1 Ki (μM)                                                                           D-2 Ki (μM)                                        ______________________________________                                        dopamine     8.0        6.3                                                   2A           0.15       >10                                                   17           0.8        >10                                                   18           1.3        >10                                                   19           0.6        >10                                                   20           1.9        >10                                                   23           0.5        >10                                                   24           0.9        >10                                                   27           >10        6.6                                                   29           6.0        >10                                                   30           >10        32                                                    35           0.03       0.76                                                  36           0.20       >10                                                   37           0.057      10                                                    38           0.12       30                                                    39           1.4        >10                                                   40           5.0        27                                                    41           0.7        2.5                                                   42           0.061      3.9                                                   43           2.4        12                                                    45           4.6        >10                                                   46           1.7        >10                                                   48           0.036      13.                                                   49           0.002      1.0                                                   50           0.007      1.2                                                   51           0.235      3.9                                                   52           0.90       6.2                                                   53           0.25       0.65                                                  54           0.004      0.91                                                  55           0.38       1.5                                                   56           2.2        1.3                                                   57           1.1        0.73                                                  58           0.26       1.2                                                   59           0.037      1.4                                                   60           0.53       2.2                                                   61           0.29       1.3                                                   62           0.21       3.7                                                   63           71         >10                                                   64           0.64       0.54                                                  65           14         16                                                    66           0.48       0.64                                                  67           1.9                                                              68           0.10       5.5                                                   69           0.087      2.7                                                   70           0.005      0.65                                                  71           15         2.8                                                   72           0.015      8.2                                                   73           0.064      34                                                    74           0.10       2.0                                                   75           0.48       4.6                                                   76           0.098      0.44                                                  77           2.3        0.50                                                  78           0.049      0.81                                                  79           0.73       0.92                                                  80           0.014      1.1                                                   81           0.21       4.6                                                   82           0.011      0.82                                                  83           2.8        4.5                                                   84           1.3        1.3                                                   85           8.1        10                                                    86           1.5        3.5                                                   87           11         0.7                                                   88           0.13       1.5                                                   89           0.021      1.4                                                   90           0.076      0.9                                                   91           0.29       >10                                                   92           1.5        5.4                                                   93           0.47       >10                                                   94           0.084      >10                                                   95           0.52       >10                                                   96           0.027      0.87                                                  97           0.071      6.0                                                   98           0.22       1.9                                                   99           0.022      8.9                                                   100          0.019      54                                                    101          0.012      0.91                                                  102          0.24       >10                                                   103          0.036      2.0                                                   104          0.037      >10                                                   105          0.017      1.0                                                   106          0.35       >10                                                   107          2.5        >10                                                   108          4.1        >10                                                   110          0.55       1.1                                                   111          0.014      0.72                                                  112          0.038      1.5                                                   113          0.22       1.4                                                   114          0.42       0.90                                                  115          12         3.0                                                   117          1.2        1.0                                                   118          2.5        6.7                                                   119          3          >10                                                   120          3.5        3.0                                                   123          8.2        >10                                                   124          1.9        0.47                                                  125          2.7        >10                                                   126          0.16       6.6                                                   127          1.3        >10                                                   128          0.57       23                                                    129          2.1        3.1                                                   130          0.051      0.19                                                  131          0.52       2.7                                                   132          0.086      0.64                                                  134          0.035      1.0                                                   135          0.18       1.6                                                   136          0.10       2.5                                                   137          2.9        0.55                                                  138          0.003      2.2                                                   139          0.45       3.2                                                   140          0.06       1.5                                                   141          0.12       2.6                                                   142          0.19       >10                                                   143          1.2        >10                                                   144          0.10       0.091                                                 145          0.067      12                                                    146          0.049      1.4                                                   147          0.40       >10                                                   148          0.064      4.6                                                   148A         0.71       2.6                                                   149          0.46       19                                                    150          0.025      12                                                    151          5.8        2.5                                                   152          59         12                                                    153          0.85       >10                                                   154          1.4        17                                                    155          2.6        8.2                                                   156          6.3        16                                                    157          1.3        16                                                    158          2.3        6.0                                                   159          3.1        3.7                                                   160          1.3        1.7                                                   161          1.3        0.17                                                  162          0.67       0.71                                                  163          0.79       0.83                                                  164          3.6        0.25                                                  165          1.8        17                                                    166          4.8        2.4                                                   167          0.31       0.0021                                                168          17         >10                                                   169          8.0        >10                                                   170          0.57       0.14                                                  171          0.53       0.81                                                  172          1.1        >10                                                   173          3.6        14                                                    174          1.2        3.5                                                   176          0.65       2.6                                                   177          0.13       6.6                                                   178          7.3        >10                                                   179          0.063      1.3                                                   180          1.1        4.7                                                   181          0.39       4.6                                                   182          0.28       2.2                                                   183          6.5        >10                                                   184          0.07       >10                                                   186          1.9        34                                                    187          2.5        6.4                                                   188          2.0        7.0                                                   189          3.3        >10                                                   190          0.33       6.3                                                   191          1.1        >10                                                   192          3.2        >10                                                   193          0.65       3.2                                                   194          4          >10                                                   195          0.25       3.3                                                   196          6.0        >10                                                   197          0.88       >5                                                    198          3.7        >10                                                   199          0.054      1.4                                                   200          0.038      3.3                                                   201          0.045      1.5                                                   202          0.20       1.6                                                   203          1.0        4.3                                                   204          0.16       1.5                                                   205          0.21       1.5                                                   206          0.026      1.6                                                   207          0.07       1.2                                                   208          0.53       3.1                                                   209          0.49       2.8                                                   210          0.047      1.3                                                   211          0.58       >10                                                   212          0.63       0.70                                                  214          0.02       5.2                                                   215          0.02       0.80                                                  216          0.003      3.7                                                   217          0.03       1.0                                                   218          0.02       0.41                                                  219          4.0        1.6                                                   220          0.41       3.1                                                   221          0.09       >10                                                   222          0.01       3.2                                                   223          0.04       2.7                                                   224          0.23       2.3                                                   225          0.09       1.7                                                   226          0.02       1.5                                                   227          0.02       >10                                                   228          0.03       >10                                                   229          0.26       3.6                                                   230          0.026      >10                                                   231          0.30       >10                                                   232          3.8        >10                                                   233          3.2        >10                                                   234          3.9        >10                                                   235          0.55       >10                                                   236          4.4        >10                                                   237          6.5        >10                                                   238          5.1        >10                                                   239          0.04       2.0                                                   240          0.75       5.2                                                   241          0.40       2.9                                                   242          1.50       2.0                                                   243          0.07       3.0                                                   244          0.24       1.2                                                   245          0.35       0.18                                                  246          0.19       3.2                                                   247          0.02       1.8                                                   248          0.58       0.88                                                  249          0.05       0.60                                                  250          0.15       1.6                                                   251          0.53       1.2                                                   252          1.0        >10                                                   ______________________________________                                    

EXAMPLE 254 In Vitro Assay of Intrinsic Activity

The interaction of dopamine or a dopamine D-1 receptor agonist with theD-1 receptor causes a dose-dependent increase in the adenylatecyclase-catalyzed conversion of adenosine triphosphate (ATP) to cyclicadenosine monophosphate (cAMP). The functional activity of the compoundsof the invention was determined by assaying, in vitro, their ability toeither stimulate the enzyme adenylate cyclase to produce more cAMP(agonist activity) or to antagonize a dopamine-induced increase in cAMPlevels. The protocol for the adenylate cyclase assays was described byK. J. Watling and J. E. Dowling in J Neurochemistry 36:559 (1981) and byJ. W. Kebabian et al. in Proc Natl Acad Sci, USA 69:2145 (1972). Inorder to determine agonist activity, cell-free tissue homogenates areincubated in an ionic buffer solution containing ATP and the compoundbeing evaluated. The tissue was obtained from either goldfish retina orrat striatum.

Table 18 shows the intrinsic activity in an adenylate cyclase assayindicating that the compounds of the present invention are dopamineagonists.

                  TABLE 18                                                        ______________________________________                                        Agonist Activity in Adenylate Cyclase Assay                                   Example #    EC50 (μM)                                                                            Intrinsic Activity                                     ______________________________________                                        dopamine     2.5       100                                                    2A           0.043     56                                                     17           2.8       42                                                     18           1.5       46                                                     20           0.5       80                                                     23           1.1       65                                                     24           0.5       71                                                     27           0.2                                                              29           1.0       54                                                     35           0.010     66                                                     36           0.079     57                                                     37           0.031     56                                                     38           0.033     91                                                     39           0.05      84                                                     40           1.1       86                                                     41           1.8       81                                                     42           0.006     98                                                     43           0.15      70                                                     45           0.06      62                                                     46           0.22      69                                                     48           0.019     112                                                    49           0.0024    66                                                     50           0.005     71                                                     51           0.18      88                                                     52           0.071     65                                                     53           0.023     67                                                     54           0.002     71                                                     55           0.024     51                                                     56           0.43      46                                                     57           0.030     56                                                     58           0.019     63                                                     59           0.006     92                                                     60           0.037     93                                                     61           0.006     76                                                     62           0.17      111                                                    63           0.71      43                                                     64           0.39      80                                                     65           0.32      91                                                     66           0.013     84                                                     67           0.23      92                                                     68           0.014     90                                                     69           0.072     108                                                    70           0.004     110                                                    71           0.71      66                                                     72           0.17      80                                                     73           0.16      138                                                    74           0.84      105                                                    75           0.29      60                                                     76           0.0058    122                                                    77           0.093     107                                                    78           0.015     147                                                    79           0.007     151                                                    67           0.008     161                                                    81           0.067     61                                                     82           0.007     107                                                    83           0.30      64                                                     84           0.11      72                                                     85           0.65      68                                                     86           0.081     87                                                     87           0.05      54                                                     88           0.012     133                                                    89           0.007     130                                                    90           0.022     128                                                    91           0.67      135                                                    92           0.60      69                                                     93           0.11      113                                                    94           0.071     110                                                    95           0.10      104                                                    96           0.25      99                                                     97           0.055     187                                                    98           0.018     108                                                    99           0.005     134                                                    100          0.019     112                                                    101          0.032     119                                                    102          0.054     113                                                    103          0.013     88                                                     104          0.054     110                                                    105          0.009     110                                                    106          0.004     65                                                     107          0.24      85                                                     110          0.088     135                                                    111          0.0013    106                                                    112          0.008     124                                                    113          0.058     60                                                     114          0.06      60                                                     115          2.2       68                                                     117          0.08      60                                                     118          0.056     87                                                     119          0.060     66                                                     120          1.1       64                                                     121          21        51                                                     123          0.77      61                                                     125          1.0       63                                                     126          0.046     94                                                     127          0.52      55                                                     128          0.087     108                                                    129          1.0       97                                                     130          0.17      82                                                     131          0.27      42                                                     132          0.87      106                                                    134          0.004     81                                                     135          0.007     136                                                    136          0.005     133                                                    137          1.0       93                                                     138          0.051     157                                                    139          0.0097    129                                                    140          0.0084    113                                                    141          0.080     97                                                     142          0.087     71                                                     143          1.1       94                                                     144          0.032     107                                                    145          0.038     49                                                     146          0.12      82                                                     147          0.066     89                                                     148          0.022     79                                                     149          0.036     78                                                     150          0.006     102                                                    151          7.0       58                                                     153          3.1       53                                                     154          0.10      95                                                     155          0.15      95                                                     156          9.5       127                                                    157          0.52      111                                                    158          0.33      100                                                    159          0.15      129                                                    160          0.14      136                                                    161          0.45      58                                                     162          0.69      107                                                    163          1.45      140                                                    164          0.20      96                                                     165          0.031     105                                                    166          0.18      97                                                     167          0.12      125                                                    168          0.27      103                                                    169          0.20      150                                                    170          0.13      151                                                    171          0.18      124                                                    172          0.22      116                                                    173          0.39      63                                                     174          0.065     90                                                     176          0.32      90                                                     177          0.17      62                                                     178          8.6       99                                                     179          0.01      107                                                    180          0.08      71                                                     181          0.017     65                                                     182          0.021     65                                                     183          0.60      56                                                     184          0.022     47                                                     186          1.3       95                                                     187          1.2       70                                                     189          1.5       65                                                     190          0.11      92                                                     191          1.5       58                                                     193          0.68      63                                                     194          0.058     82                                                     195          0.40      73                                                     196          1.1       80                                                     197          0.18      56                                                     199          0.033     83                                                     200          0.033     120                                                    201          0.0036    110                                                    202          0.078     84                                                     203          >10       0                                                      204          0.048     110                                                    205          0.068     100                                                    206          0.068     79                                                     207          0.027     64                                                     209                    25                                                     210          0.052     98                                                     211          0.063     38                                                     212          0.48      43                                                     213                    70                                                     214          0.02      106                                                    215          0.02      114                                                    216          0.005     114                                                    217          0.02      108                                                    218          0.01      115                                                    220          0.40      72                                                     221          0.08      84                                                     222          0.04      87                                                     223          0.07      52                                                     224          0.24      64                                                     225          0.13      76                                                     226          0.04      89                                                     227          0.37      94                                                     228          0.28      71                                                     229          0.33      34                                                     230          0.12      59                                                     231          0.09      85                                                     232          1.7       49                                                     234          2.7       53                                                     235          0.30      83                                                     236          0.70      36                                                     237          1.9       34                                                     239          0.04      103                                                    240          0.13      70                                                     241          0.40      48                                                     243          0.95      83                                                     246          0.22      78                                                     247          0.03      75                                                     249          0.20      32                                                     251          0.47      41                                                     252          1.7       49                                                     ______________________________________                                    

EXAMPLE 255 Rotation Behavior Assay of In Vivo Activity

The behavioral assay used was based on the rat rotational model.Striatal dopamine was depleted by the intracranial injection of6-hydroxydopamine, a neurotoxin which specifically destroyscatecholaminergic neurons. The intracranial injection was conducted onanesthetized animals using standard stereotaxic techniques (U.Ungerstedt and G. W. Arbuthnott, Brain Research 24: 485, 1970, and U.Ungerstedt, Acta Physiol. Scand. Suppl. 367, 69: 1973). This unilaterallesioning of dopamine-containing neurons causes the post synapticdopamine receptors to become supersensitive to dopaminergic stimulationin behavioral assays. When these striatal dopamine receptors arestimulated by the test compounds, the rats rotate or physically turn, ina direction that is away from the side of their body that receives thegreater dopaminergic activation due to the receptor supersensitivity.Agonist activity was measured by the ability of the test compound toinduce rotation.

The results of this testing, shown in Tables 19 and 20, demonstrate therotation behavior of selected compounds of the present invention.

                  TABLE 19                                                        ______________________________________                                        Rotation Behavior                                                             Example No.                                                                             ED50 (mmol/kg) s.c.*                                                                         ED50 (mmol/kg) oral                                  ______________________________________                                        2A        1.2            27                                                   3         0.91                                                                35        --             21.4                                                 36        0.5            170                                                  48        0.12           --                                                   49        0.39           19.5                                                 50        0.35           10.9                                                 55        13.6           --                                                   59        1.02           29.5                                                 51        7              --                                                   64        58             --                                                   86        0.45           >37                                                  88        0.61           32                                                   89        0.12           7                                                    90        0.6            8                                                    93        0.9            --                                                   100       0.12           --                                                   103       0.05           8                                                    104       0.13           5                                                    105       0.17           --                                                   111       0.25           6.25                                                 112       0.10           1.0                                                  126       0.16           28                                                   130       0.13           8                                                    138       0.15           --                                                   139       0.4            23                                                   145       0.31           --                                                   146       0.12           7                                                    147       0.05           --                                                   148       0.12           11                                                   199       1.5            31                                                   200       0.7            19                                                   201       0.34           --                                                   204       1.1            18                                                   205       3.4            --                                                   210       0.005          1.6                                                  214       0.085                                                               215       0.55                                                                216       0.07                                                                217       0.12                                                                218       0.93                                                                219       0.09                                                                220       0.52                                                                221       >3                                                                  222       0.3                                                                 223       >3                                                                  225       >3                                                                  226       >1                                                                  227       0.045                                                               228       0.1                                                                 231       >3                                                                  239       >3                                                                  240       >3                                                                  241       >3                                                                  244       >3                                                                  246       0.54                                                                247       0.014                                                               249       0.12                                                                250       0.51                                                                ______________________________________                                         *injected subcutaneously                                                 

                  TABLE 20                                                        ______________________________________                                        Rotation Behavior                                                             Example Number                                                                             mean rotations over 360 minutes*                                 ______________________________________                                        4            3329                                                             6              2564**                                                         10           1516                                                             14           3653                                                             15           1760                                                             16           4844                                                             ______________________________________                                         *dose = 143 micromoles/kg p.o.                                                **mean rotations over 20 hours                                           

EXAMPLE 256 Cardiovascular Pharmacology--Hemodynamic Studies inAnesthetized Dogs

Male Beagle dogs were anesthetized with pentobarbital (30 mg/kg. i.v.)and maintained with i.v. infusion (Abbott/Shaw Life Care Pump, ModelII/D) to maintain stable cardiovascular function. The dogs wereincubated with a cuffed endotracheal tube and ventilated with room airby means of a positive pressure respiratory pump. Expired respiratoryCO₂ was monitored with a Beckman LB-2 gas analyzer and maintained at 5%by appropriate pump adjustments. The dogs were maintained at a bodytemperature of 37.5°±1.0° C. with a thermostatically controlled animaltable. Polyethylene catheters were placed in the abdominal aorta via thefemoral and carotid arteries for blood pressure and left ventricularpressure recordings. A Swan-Ganz thermodilution catheter with a 15 cmproximal port was placed in the jugular vein for central venous andpulmonary arterial recordings and for determination of cardiac output(American Edwards Cardiac Output Computer, Model COM-1). Heart rate andelectrocardiogram (ECG) recordings were made from a Lead II ECGconnection. With the dog on its fight side the abdominal cavity wassurgically entered laterally, immediate inferior to the rib cage, toexpose the left renal artery. A calibrated electromagnetic flow probe(Carolina Medical Electronics) was positioned around the renal artery.The abdominal cavity is closed with wound clips. Recordings were made ona Grass polygraph.

An additional small polyethylene catheter was inserted into a branch ofthe left femoral artery and the tip positioned in the aorta above therenal arteries. Compounds were continuously infused intrarterially(Harvard Infusion Pump, Model 975) for approximately 5 minutes per dose.A thirty-fold dose-response-curve was administered by varying flow ratefrom 0.01 to 0.30 mL/minute.

Table 21 below shows the effects of selected compounds of the presentinvention on cardiovascular pharmacology.

                  TABLE 21                                                        ______________________________________                                        Effects Of Selected Dopaminergic Agonists On The                              Renal Blood Flow (RBF) And Mean                                               Arterial Blood Pressure (MAP) In Anesthetized Dogs                                    Dose range                                                                              Max Increase RBF                                                                            Max Decrease                                  Example #                                                                             g/kg/min  (%)           MAP (%)                                       ______________________________________                                        2A      3-10      27            32                                             3      1-10      83             8                                            35      1-3       35            26                                            36      1-10      94            13                                            37      1-30      48            39                                            ______________________________________                                         *Cumulative intraaortic (above renal) infusion                           

EXAMPLE 257 Diuretic Effects in Spontaneously Hypertensive Rats

Male, spontaneously hypertensive rats (SHR), weighing 285-350 grams wereused to evaluate the diuretic effects of one of the compounds of theinvention. Following an overnight fasting period with free access todrinking water, the rats received an intragastric fluid load of 0.9saline at 5% of their body weight. Simultaneously with the load, therats were dosed with a test compound or vehicle and placed individuallyin stainless steel metabolic cages where they had access to drinkingwater throughout the duration of the experiment. For intravenousadministration, the rats were instrumented with indwelling cannulasplaced into the jugular vein at least one week prior to the experiment.

Urine was collected at 2 and 4 hours following drug administration. Thevolume of excreted urine at each collection interval was measuredaccurately and the samples were analyzed for sodium, potassium andchloride ions. Sodium and potassium were measured using a DigitalReadout Flame Photometer (Instrumentation Labs). Chloride was measuredby the method of Shales and Shales, J Biol Chem 140:879 (1941). Thestatistical analysis of the data was computed by an off-line computerprogram. In this program, a comparison test is made between the vehicle(control) group and each treatment group for all variables at each timeinterval of the experiment. The test of statistical significance isbased on the Student's t-test, where the calculated t is a measure ofthe probability density function.

The compound of Example 2A was administered to six rats intravenously ata dose of 0.3, 1.0 and 3.0 mg/kg. A control group of six rats received0.1 mg/kg of saline solution acidified by ascorbic acid (0.3 mL). Thissolution was also the vehicle for the test compound.

Table 22 shows the diuretic and saliuretic effects of the compound ofExample 2A.

                  TABLE 22                                                        ______________________________________                                        Diuretic Effects of 3.0 Mg/Kg in Hydrated Spontaneously                       Hypertensive Rats                                                                      Urine Analysis At 2 Hour Interval After                                       Administration                                                                                 Po-                                                         Volume   Sodium   tassium                                                                              Chloride                                                                             Na/K                                  Sample  (mL/kg)  (meq/kg) (meq/kg)                                                                             (meq/kg)                                                                             Ratio                                 ______________________________________                                        Control 13.02    1.60     0.29   1.87   9.99                                  Group                                                                         Example 22.57    2.35     0.55   2.71   5.06                                  2A Group                                                                      Control 4.29     0.59     0.17   0.83   10.27                                 Group SD                                                                      Example 8.30     0.84     0.22   0.75   2.85                                  2A Group                                                                      SD                                                                            p < = 0.05                                                                            0.0313*  0.1043   0.0423*                                                                              0.0950 0.28134                               ______________________________________                                         *statistically significant, n = 6                                        

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

What is claimed is:
 1. A process for preparing a compound according toformula ##STR341## wherein R¹ is a catechol-protecting group, and R¹⁸ issubstituted C₃ -C₉ -alkyl, comprising the steps of (a) reacting anintermediate having the formula ##STR342## where R¹ is acatechol-protecting group, with a strong base to form a chiral epoxideof the formula ##STR343## and (b) reacting the epoxide with anorganometallic substituted C₃ -C₉ -alkyl compound in a non-polar organicsolvent to provide the compound.